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The vitamins and minerals that help the immune system respond to respiratory viruses – Dec 2022


How Micronutrients Fuel Immune System at the Molecular Level: An Approach to the Immune Response Against Respiratory Viruses

Cell Physiol Biochem 2022;56(S1):53-88 DOI: 10.335944000000591
Alexis Paulina Jiménez-Uribe Ariana Ocampo-Hernández Yalith Aranciba-Hernández José Pedraza-Chaverri
Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, México City, México

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Abstract
Viral respiratory infections could range from a common cold to severe pneumonia, and their resolution mainly relies on appropriate immune system function. The widespread popular knowledge that nutritional habits influence immune system function has been demonstrated over the past decades in which increasing scientific evidence unveils certain nutrients as critical drivers of immunity. Micronutrients encompass minerals and vitamins necessary for a broad range of biological processes; since their deficiency could cause several clinical manifestations, such as weakness, growth retardation, and susceptibility to infections; hence, micronutrients represent one of the multiple factors that modulate immune function. Among micronutrients are those that act mainly as antioxidants, regulating gene expression and as a structural part of proteins for their proper function. Here, we review how some of the most recognized micronutrients are participating at the molecular level in each step of the innate and adaptive immune response against viruses focusing on viral respiratory tract infections, such as those caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
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Introduction

Respiratory tract infections (RTI) can range from a self-limiting cold to severe pneumonia with sepsis development [1]. Although several etiologies exist, viruses have gained significant attention due to the current global sanitary situation caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2]. Among causal viruses of RTI, besides SARS-CoV-2 and other coronaviruses, are the enterovirus, respiratory syncytial virus (RSV), metapneumovirus, rhinovirus, parainfluenza virus, influenza virus, and adenovirus [2].
Despite the causal virus and the pathogenic evasion mechanisms of each one, all of them evoke the activation of the innate and adaptive immune response, which in general involves the following steps:

  • 1.) The epithelial barrier is the first defense restricting infections; the airway epithelial barrier performs mechanical actions such as cilia movement and warming air; this also contains in the airway liquid surface (ALS) mucins (MUC) and antimicrobial peptides (AMP), molecules which help to reduce the possible infection.
  • 2.) Once viruses bypass epithelial barrier actions and molecules, they infect target cells and cause cellular stress. In response, host cells will use their pattern recognition receptors (PRRs) to recognize viral pathogen-associated molecular patterns (PAMPs), triggering an antiviral alarm state in which interferons (IFN) type I and III are synthesized, natural killer (NK) cells are activated, and inflammation is generated. At this time-point viral infection might resolve, but if that is not, the antigen-presenting cells (APC) are ready to trigger the next steps.
  • 3.) APC such as macrophages and dendritic cells (DC) process endogenous and exogenous antigens to further present them on their major histocompatibility complex (MHC) molecules class I or II, respectively. Antigens loaded on MHC-I molecules are presented to the T cell receptor (TCR) of T cytotoxic (Tc) CD8+ lymphocytes, whereas antigens loaded on MHC-II are presented to the TCR of T helper (Th) CD4+ lymphocytes, giving rise to the adaptive immune response.
  • 4.) Tc CD8+ lymphocytes are the major players in the adaptive cellular response that aims to kill infected cells. On the other hand, Th CD4+ lymphocytes could also participate in cellular response; however, they mainly cooperate with B lymphocytes to elicit the adaptive humoral response characterized by antibody production [3].

The expected result of the antiviral immune response is the control and elimination of the pathogen (Fig. 1 and 2); however, some factors could affect the infection resolution, such as evasion mechanisms of the viruses, stress, environmental pollution, hormonal status, comorbidities, and nutrition [4-10].

Fig. 1. Innate immune response

Innate immune response against respiratory viruses. a) The mucins (MUC) and antimicrobial peptides (AMP) that are present on the airway epithelial barrier; the type I and III interferons (IFN) produced by the recognition of viral components by the pattern recognition receptors (PRRs); the activation of the Janus kinase (JAK)/ signal transducer, and activator of transcription proteins (STAT)/in- terferon regulatory factors (IRF) pathway in the neighboring cells; the activation of natural killer (NK) cells; the induction of inflammatory response; and the activation of antigen-presenting cells (APC) are part of the innate immune response against respiratory viruses. Figure created with BioRender.com.

Fig. 2. Adaptive immune response

Adaptive immune response against respiratory viruses. The adaptive cellular response involves the presentation of endogenous antigens onto the major histocompatibility complex (MHC)-I molecules to T cytotoxic (Tc) CD8+ lymphocytes, which aim to kill the infected cell. In contrast, the adaptive humoral response involves the presentation of exogenous antigens onto the MHC-II molecules to the T helper (Th) CD4+ lymphocytes and their cooperation with B lymphocytes that subsequently produce antibodies to neutralize viruses, induce the classical pathway of complement, or trigger the antibody-dependent cellular cytotoxicity (ADCC). Figure created with BioRender.com.

ADAPTIVE IMMUNE RESPONSE AGAINST RESPIRATORY VIRUSES
In this regard, SARS-CoV-2 infection causes a severe inflammatory response in patients with comorbidities such as diabetes, hypertension, and obesity [11], pathologies tightly related to metabolic and nutritional alterations.
Indeed, micronutrient imbalance is associated with the risk of complicated respiratory tract infections, as has been reported for vitamins A, D, E, and C and the trace elements zinc and magnesium [12-20]; therefore, their supplementation improves the effector function of the immune system, as has been excellently reviewed elsewhere [21, 22]. Here we will focus on how those micronutrients mentioned above, in which deficiency or supplementation impacts immune function, participate at the molecular level in each step of the immune response against respiratory viruses. Considering their three main action mechanisms as antioxidants, gene-expression regulators, and structural components of proteins, we will revise their functions as immuno-stimulators, immuno-regulators, or even both.

General overview of micronutrients

Micronutrients encompass vitamins and minerals typically considered cofactors involved in many enzymatic reactions; however, they perform several other functions. For example, vitamins C and E act as antioxidants, vitamins A and D regulate the expression of several genes, and the trace elements zinc and magnesium are structural parts of transcriptional factors (Fig. 3).
•*1.) Antioxidant vitamins: Oxidative stress is a typical process occurring during respiratory viral infections that requires to be tightly regulated to avoid its contribution to the pathology progression [23]. The two vitamins, well known for their antioxidant properties, vitamins C and E, are also involved in each step of the immune response through their antioxidant and other mechanisms.
Vitamin C, also known as ascorbate or its oxidized form dehydroascorbate (DHA], is taken up by cells via sodium-dependent vitamin C transporters (SVCT) and glucose transporters (GLUT] [24]; in immune cells, SVCT2 and GLUT3 seem to be especially relevant for vitamin C uptake, and the contribution of each one depends on the lineage and differentiation status [25-27].

Fig. 3. Action mechanisms of micronutrients

Action mechanisms of micronutrients, in addition to being cofactors. Vitamin A (Vit. A) is metabolized to retinaldehyde and retinoic acid (RA); which is recognized through the RA receptor (RAR) that, in turn, interacts with the retinoid X receptor (RXR);
RAR/RXR dimer functions as a transcriptional factor that binds genes containing RA response elements (RARE). The active form of vitamin D (Vit. D) binds to the vitamin D receptor (VDR), which also interacts with RXR, functioning also as a transcriptional factor that binds to genes containing vitamin D response elements (VDRE). Vitamin E (Vit. E) can be part of the plasma membrane to regulate its curvature, acts as an antioxidant, and can be metabolized to carboxychromanols which exert other functions. Vitamin C (Vit. C) is an antioxidant and a cofactor of several alpha-ketogluta- rate-dependent dioxygenases (aKGD), enzymes that regulate epigenetics and metabolism. Zinc (Zn) and magnesium (Mg) interact with and support the function of many biomolecules, mainly proteins such as enzymes and transcriptional factors. Figure created with BioRender.com.
The antioxidant function of vitamin C relies on its electron donor capacity but also functions as a metabolic and epigenetic modulator through the alpha-ketoglutarate- dependent dioxygenases (aKGD), enzymes that use this vitamin as a cofactor [28-30].
On the other hand, vitamin E embraces eight lipophilic molecules sharing a chromanol ring structure, four tocopherols isomers (a, p, y, 5) and four tocotrienols isomers (a, p, y, 5); these can be distinguished among them by the number of bonds of the side chain and by the methyl groups in the chromanol ring structure. Due to its chemical nature, vitamin E could easily conjugate with lipophilic compounds such as bile acids, cholesterol, and other lipids and is taken up by cells mainly through the scavenger receptor B type I (SR-BI) but also by the cluster of differentiation (CD)36 [31-33]. Interestingly, CD36 is a molecule highly expressed on phagocytic cells such as neutrophils, monocytes, and macrophages; and its expression is affected by respiratory viruses, as has been reported for influenza virus and RSV infections in vitro [34, 35]. Once inside cells, vitamin E is transformed into carboxychromanol (COOH) metabolites through different steps of oxidation and shortening the side chain length [31, 32].
Besides its chromanol ring structure-dependent antioxidant function, other functions of this vitamin are to regulate plasma membrane curvature under stress conditions, modulate the inflammatory process, and even suggest controlling gene expression through the pregnane X receptor (PXR) [36-40].

  • 2.) Gene-regulating vitamins: The liposoluble vitamins A and D can bind to their receptors to activate their transcriptional factor function and promote the expression of several genes, including some involved in the innate and adaptive immune responses. Vitamin A, also referred to as retinol, requires to be transported by the retinol-binding protein (RBP) to enter cells by passive diffusion or through the receptors SR-BI, adenosine triphosphate (ATP)-binding cassette transporter (ABCA4), and stimulated by retinoic acid gene 6 (STRA6) [41, 42]. Inside cells, retinol is metabolized to retinaldehyde and retinoic acid (RA) through retinol dehydrogenase and retinaldehyde dehydrogenase, respectively. While retinaldehyde is involved in the visual cycle, RA regulates the expression of several genes through its recognition by the RA receptor (RAR). RAR, together with the retinoid X receptor (RXR), functions as a transcriptional factor when bound to hundreds of genes that contain RA response elements (RARE] [41]; among these are immune response genes, such as the RA inducible gene-I (RIG-I), a PRR that recognizes viral RNA; and the 2’-5’-oligoadenylate synthase 1 (OAS1), a protein involved in the viral RNA degradation [43, 44].

Vitamin D can be acquired from dietary sources as vitamin D2 (ergocalciferol) from plants or as vitamin D3 (cholecalciferol) from animals; however, its primary source is the 7-dehydrocholesterol in the skin, which is converted to vitamin D3 by the action of ultraviolet light. Vitamin D is transported by the vitamin D binding protein (DBP) to the liver, where hepatocytes convert it to 25-dihydroxy vitamin D3 (25(OH)D3 to then reach the kidneys, where tubular cells transform it into the active form of vitamin D, the 1,25-dihydroxy vitamin D3 (1,25(OH)2D3). Interestingly, some immune cells, such as macrophages, dendritic cells, and T cells, can also produce the active form of vitamin D [45-47].
The active form of vitamin D acquired or synthesized by cells is recognized by the vitamin D receptor (VDR), which also interacts with RXR to function as a transcriptional factor that binds several genes containing vitamin D response elements (VDRE) to regulate their expression [48]. The most know function of vitamin D is the induction of the expression of the transient potential vanilloid type 6 (TRPV6) required for the promotion of calcium absorption; however, it also promotes the expression of several genes associated with immunoregulatory functions [49].
•*3.) Structural trace elements: Zinc and magnesium are two metals that stabilize the structure of hundreds of biomolecules, mainly proteins, and therefore allow them to function.
Zinc is one of the most relevant metals in the organism; estimating that it interacts with near of 10% of the human proteome, mainly enzymes and transcriptional factors [50, 51]. Zinc is taken up by cells through the Zrt/Irt-like proteins (ZIP), intracellularly this mineral is found inside organelles and vesicles or bound to proteins named metallothioneins (MT); and its concentration is regulated by the ZIP-dependent uptake, as well by its release through the zinc transporters (ZnT) [52]. A relevant finding from nearly two decades ago is that zinc deficiency affects immune system development, causing thymic atrophy in rodents [53, 54] since the zinc-dependent hormone thymulin produced by thymic epithelial cells is necessary for proper T lymphocyte development [55, 56].
On the other hand, magnesium is well known for its participation in stabilizing DNA, its requirement for DNA polymerase reactions, and for being bound to ATP, facilitating the phosphate group transference; however, as occurs with zinc, it participates in several cellular processes due to its interaction with hundreds of proteins. Different transporters take up this metal in immune cells, such as the transient receptor potential cation channel subfamily M (TRPM)6 and 7, the solute carrier family 41 members 1 and 2 (SLC41A1/A2), and the magnesium transporter 1 (MAGT1) [57, 58]. Among its different functions, the involvement of magnesium in immune response was initially discovered because a defect in its transport due to a mutation of the MAGT1 gene in humans causes a combined immunodeficiency mainly affecting T lymphocytes response [59].

Functions in airway epithelial barrier

The respiratory tract is a tightly impermeable barrier covered by ALS, which plays a fundamental role in clearing pathogens and other foreign molecules. ALS is composed of several substances, including MUC and AMP.
In vitro, MUC homogenates have been reported to restrict infection of several viruses in epithelial cell cultures [60], particularly MUC1 interacts with the influenza virus and restricts the infection in lung epithelial cells in vitro and in vivo [61], also decreases the production of the pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) in RSV-infected lung epithelial in vitro [62]. Although there is no evidence yet of the effect of MUC1on SARS-CoV-2 replication, severe COVID-19 patients show increased levels of this in bronchial mucus [63].
On the other hand, the p-defensins (BD) are AMP widely expressed in epithelia that, in addition to their antibacterial functions, can also interact with viruses to prevent their entry into the host cells. Mouse BD (MBD) 3, MBD4, and a fusion peptide that contains MBD1 and MBD3 have been reported that interact with the influenza virus and impair the experimental infection in vitro and in vivo [64-66]. Similarly, human BD (HBD) 2 has been reported to disrupt the envelope of RSV, reducing its infection in vitro [67]. A short peptide derived from MBD4 named P39 also has been shown to decrease in vitro infection with the influenza virus, middle east respiratory syndrome (MERS)-CoV, and SARS-CoV, although interaction with the viruses is still unexplored [68]. Another interesting function of BD is enhancing antibody production, as has been demonstrated for HBD2 and MBD2 in mice immunized with MERS- CoV spike (S) protein and influenza virus [69, 70].
BD has not been reported to have a direct effect on SARS-CoV-2; however, the human neutrophil peptides (HNPs) 1, 2, and 3, and the human defensin (HD) 5, all of them a-defensins (AD), have shown to limit the infection in vitro [71]. AD are found mainly in neutrophil granules [72]; therefore, their release involves neutrophil activation and degranulation, although this has been associated with poor outcomes in COVID-19 patients [73].
Cathelicidins are another type of AMP found in neutrophil granules involved in protection against respiratory viruses since they have been shown to limit RSV and influenza virus infection in vitro and in vivo by disrupting viral membranes [74-77]. Human, porcine, and ovine cathelicidins also have been reported to diminish rhinovirus infection in vitro [78]; however, an evasion mechanism of rhinovirus to avoid cathelicidins function is to modify their cationic to a neutral charge [79]. In the case of SARS-CoV-2, it has been reported that human cathelicidins interact with the viral S protein restricting the in vitro and in vivo infection [80].
Among the micronutrients that support the airway epithelial barrier integrity and the production of MUC and AMP with antiviral activity are vitamins A, D, E, C, and zinc (Fig. 4).
Vitamin A is relevant in embryogenesis, particularly in the respiratory tract; its deficiency causes malformations in the trachea, lung, and smooth muscle [41, 81]. In mature airways, this vitamin has been shown to participate in tissue remodeling upon injury, promoting the activation of the mitogen-activated protein kinase (MAPK) and modulating the extracellular matrix composition [82-84]; while, through RAR/RXR activation can promote the expression of MUC2, MUC5A, MUC5B, and cathelicidins in airway epithelial cells [85-87].

Fig. 4. airway epithelial barrier.

Micronutrients functions in the airway epithelial barrier.
Vitamin A (Vit. A) induces the expression of mucins (MUC) and antimicrobial peptides (AMP); it also promotes the mitogen-activated protein kinase (MAPK)/extracellu- lar signal-regulated kinase (ERK) pathway upon injury to promote tissue remodeling. Vitamin D (Vit.D) influences the expression of AMP Vitamin E (Vit. E) can be part of the plasma membrane regulating its fluidity, blocking bioactive phospholipids, and mitigating reactive oxygen species (ROS). Vitamin C (Vit. C) also functions as an antioxidant, participates during collagen synthesis for tissue remodeling, and promotes cystic fibrosis transmembrane conductance regulator (CFTR) activity, a channel that induces chloride secretion and hydrate airway liquid surface (ALS) and MUC. Zinc (Zn) is necessary to preserve tight junctions in the epithelial barrier. Figure created with BioRender.com.
Bioactive

The antioxidant function of vitamin E indirectly modulates the inflammatory response in airway epithelium [93] and, as a component of the plasma membrane, has been shown to contribute to its fluidity and that interact and neutralize dangerous lipids such as lysophosphatidylcholine and platelet-activating factor (PAF) [94], molecules released during respiratory viral infections that have been reported to promote inflammation and epithelial barrier leakage [95-97].
On the other hand, vitamin C, as vitamin A, has been demonstrated to be relevant for proper healing since, during airway injury, the prolyl hydroxylase (PHD]-dependent type VI collagen synthesis requires this vitamin as a cofactor [98, 99]. In the ALS, vitamin C has been discovered that promotes the activation of the cystic fibrosis transmembrane conductance regulator (CFTR], a channel that elicits chloride secretion for fluid hydration in nasal and tracheal epithelial cells [100]; therefore, since MUC are released as dehydrated polymers, vitamin C indirectly impacts on MUC fluidity [101].
Under stress conditions, it has been described that airway epithelial cells increase zinc uptake through the ZIP8 transporter, hypothesizing that it functions as a second messenger to maintain the barrier impermeability; since zinc depletion causes paracellular permeability due to reduced levels of the thigh junctions proteins zonula occludens-1 (ZO-1) and claudin-1 [102, 103].

Roles in the antiviral response mediated by interferons (IFN)-I

Viruses infect using different host cell receptors, as has been reported for CoV through ACE2 [104]; RSV through C-X3-C Motif Chemokine Receptor 1 (CX3CR1] [105]; influenza virus, parainfluenza virus, and enterovirus through sialic acid [106-108]; metapneumovirus through integrins [109]; rhinovirus through low-density lipoprotein receptor (LDLR] and very-LDLR (VLDLR] [110]; and adenovirus through desmoglein [111].
Once inside, viral nucleic acids can be recognized by different PRRs. For example, singlestrand (ss) RNA could be identified by toll-like receptor (TLR] 7, TLR8, and nucleotidebinding oligomerization domain-containing protein 2 (NOD2); double-strand (ds)RNA could be recognized by retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and TLR3; moreover, other receptors such as the NOD-like receptor family pyrin domain-containing (NLRP) 1 and NLRP9b also have been reported to recognize dsRNA [112, 113]. On the other hand, viral DNA is identified through TLR9, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), DExH-Box Helicase (DHX) 9, and DHX36 [114, 115].
PRRs activation triggers several signal pathways that activate transcriptional factors such as the interferon regulatory factors (IRF) and the nuclear factor kappa B (NF-kB); these transcriptional factors induce the expression of IFN-I, IFN-III, and pro-inflammatory cytokines to induce an antiviral state in the neighboring cell and promoting the inflammatory response [116, 117].
IFN-I act in paracrine through IFN a/p receptors (IFNAR), whereas IFN-III act through the IFN-A receptor (IFNLR). IFNAR and IFNLR ligation activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway to induce an antiviral state characterized by the expression of interferon-stimulated genes (ISG) [116]. Besides the antiviral state induction, IFN-I also participates in the development and modulation of NK cells [118-120], as well as in the promotion of dendritic cell maturation for a proper antigen presentation [121, 122].
IFN-I response could vary among viral challenges; for example, IFN-I pretreatment reduces straightly viral replication of SARS-CoV-2 compared to influenza and SARS-CoV in vitro [123]. However, some respiratory viruses can subvert IFN-I production through their non-structural protein 1, which has been reported for the influenza virus, RSV, and SARS CoV-2 [124-127]. Indeed, the impaired production of IFN-I has been associated with disease worsening in COVID-19 patients [128-130], probably by a delayed production, as demonstrated in a SARS-CoV mice model [131].

Fig. 5. response mediated by interferons

Roles of micronutrients in the antiviral response mediated by interferons (IFN)-I. Vitamin A (Vit. A) promotes the expression of the retinoic acid-inducible gene I (RIG-I), a receptor that detects viral double-strand (ds)RNA. Vitamin C (Vit. C) enhances interferon-stimulated genes (ISG) expression by stimulating mitochondrial metabolic changes. Zinc (Zn) is necessary for the function of the zinc finger CCHC domain-containing protein 3 (ZCCHC3), a protein that interacts with viral dsRNA to facilitate its delivery to different receptors such as RIG-I, melanoma differentiation-associated protein 5 (MDA5), and toll-like receptor 3 (TLR3). Figure created with BioRender.com.
The micronutrients implicated in stimulating the IFN-I response include vitamins A, C, and zinc (Fig. 5).
Vitamin A has been reported to enhance RIG-I expression [44, 132], a kind of PRR that recognizes influenza virus, SARS-CoV2, metapneumovirus, parainfluenza virus, and RSV [126, 133-136].
On the other hand, vitamin C has been demonstrated to enhance the expression of several ISG, including MDA-5 and RIG-I, which are involved in the viral dsRNA recognition; and Mx1, a protein that interferes with the viral polymerase activity of the influenza virus [137-139]. However, the antiviral response influenced by this vitamin could be an indirect effect since it has been reported that it preserves mitochondrial functions [140, 141] and prevent the decrease of the mitochondrial antiviral signal-protein (MAVS) induced by influenza virus infection in mice [142]. MAVS is an outer mitochondrial membrane protein necessary to anchor MDA-5 and RIG-I during their activation for IFN-I production [143].
Zinc has been reported to enhance the antiviral action of IFN-I in vitro [144]. One reported mechanism is by the action of the zinc finger CCHC domain-containing protein 3 (ZCCHC3), a protein that facilitates viral dsRNA and dsDNA delivery to different PRRs such as RIG-I, MDA5, and cGAS [145, 146]; moreover, ZCCHC3 also has been shown to promote oligomerization of RIG-I, MDA5, and TLR3 for their activation [146, 147].
Vitamin D’s role seems to be immunomodulatory since it downregulates ISG expression and IFN-I production in an NF-KB-dependent manner during RSV infection in tracheal epithelial cells without affecting viral replication [148].

Functions in NK cell differentiation and activation

Under a steady state, NK cells remain inactive due to inhibitory signals from their killer Ig-like receptors (KIR), such as NKG2A and Ly49, which recognize MHC-I molecules from self-cells in an antigen-independent manner. Although some respiratory viral infections have been reported to decrease MHC-I molecules to avoid the adaptive cellular response [149, 150], NK cells are ready to respond. These will be activated due to the loss of KIR inhibitory signals, by the recognition of molecules on infected cells by the killer activation receptors (KAR) such as NKG2D and NKp46, and through the ligation of CD16 to finally execute their cytotoxic effect on infected cells by releasing perforins and granzyme B and producing cytokines such as IFN-y [151-153].
However, some respiratory viruses subvert NK cell response, such as has been described for metapneumovirus, which reduces KAR ligands on infected cells in vitro [154]; or SARS- CoV-2, which increases surface levels of the inhibitory receptor NKG2A on NK cells, resulting in less degranulation and IFN-y production [155].
Although NK cells with an activation phenotype are necessary to eliminate infected cells, a subset of NK cells with a regulatory phenotype is also required to avoid harmful effects [156]. Indeed, enhanced NK cell numbers with activated phenotype in the lungs have been associated with severe lung injury during experimental models of influenza virus and RSV infections, probably by the exacerbated release of perforins, granzymes, and cytokines that potentiate the inflammatory response [157-159].
Several micronutrients are involved in modulating the development and function of NK cells. It has been described that vitamin D and zinc promote their differentiation; these same micronutrients, together with magnesium, favor their activation, while vitamins C, A, and zinc favor their regulation. (Fig. 6).
Vitamin A, through RAR, has been reported to decrease NK cell’s cytotoxicity and IFN-y production by diminishing granzyme B and the KAR NKp46 levels in an NF-KB-dependent manner [160]. However, long-term vitamin A deficiency in rats also has been reported to result in lower levels and function of NK cells [161, 162], thus could suggest that this vitamin is required for both NK cell regulation and activation.
Similarly, vitamin D deficiency has been associated with reduced numbers of NK cells during pneumonia-derive SARS-CoV2 infection in humans [163], probably compromising NK cell generation, since it has been demonstrated that vitamin D induces the expression of the vitamin D upregulated protein 1 (VDUP1), a protein that promotes the differentiation of NK cells [164]. On the other hand, mature NK cells treated with vitamin D have been shown to increase their KAR levels and enhance their cytotoxic activity [165]. Moreover, in vivo, vitamin D supplementation has been reported to enhance the numbers and cytotoxic function of NK cells in healthy mice but not obese mice [166]; this could suggest that in obesity, which is considered a chronic inflammatory disease, vitamin D, instead being used by NK cells, it could be used by adipose tissue to regulate its metabolism and to limit the inflammatory response [167], as will be discussed below.
Vitamin C has been reported to stimulate the proliferation of NK cells and to promote a regulatory phenotype [168] by increasing the expression of KIR through the activity enhancement of an aKGD named ten-eleven translocation (TET) demethylase, which acts on KIR promoters to elicit their transcription [169].
On the other hand, zinc has been reported to be necessary for two zinc finger transcriptional factors involved in NK differentiation, GATA binding protein 3 (GATA-3) and zinc finger E-Box binding homeobox 2 (Zeb2) [170-172].

Fig. 6. natural killer

Micronutrients functions during natural killer (NK) cell differentiation and activation. Vitamin D (Vit. D) promotes NK cell differentiation inducing vitamin D up-
regulated protein 1 (VDUP1) expression, while in mature NK cells promotes their activation by decreasing the expression of the killer Ig-like receptors (KIR). Zinc is required for the transcriptional factors GATA binding protein 3 (GATA-3) and zinc finger E-Box binding homeobox 2 (Zeb2), both involved in the NK cell differentiation; in mature NK cells, zinc has dual roles, promoting their activation by increasing perforin levels, or promoting their regulation by inducing KIR polymerization. Magnesium (Mg) promote NK cell activation by increasing killing activation receptor (KAR) levels. Vitamin C (Vit. C) and vitamin A (Vit. A) promote the regulation of NK cells by decreasing KAR levels and increasing KIR levels, respectively. Figure created with BioRender.com.

In differentiated NK cells, zinc supplementation has been demonstrated to increase perforin levels and enhance their cytotoxic effect triggered by IL-2 [151]; interestingly, zinc also has been reported to be necessary for the inhibitory signals of NK cells since it binds to the extracellular domain of KIR for their proper polymerization and inhibitory effect [173]; these findings could suggest that the effects of this metal could be different if it is found intracellularly, probably acting as a second messenger or bound to transcriptional factors; or if it is found in the extracellular environment bound to surface receptors.
Magnesium also seems to support the cytotoxic function of NK cells since it has been reported that in cells derived from magnesium-deficient patients, there is an impairment in their functionality, which can be reversed by in vitro supplementation with this trace element by increasing KAR levels and restoring the cytotoxic function [174].

Functions in the inflammatory response

Inflammation involves a series of vascular and cellular events in response to external or internal dangerous stimuli, which aims to eliminate or control them until the tissue homeostasis is recovered; hence, during a normal process, the onset phase is followed by the resolution phase. A wide variety of mediators participate during this process, including those already pre-formed and released immediately, those quickly generated by enzymatic reactions, and those transcriptionally induced by an upstream signal such as PRRs ligation; together, all of these mediators act on endothelial, tissue, and immune cells to drive their function [175, 176].
During the onset phase, vasodilation is one of the first events in which mast cells and platelets release histamine; this already pre-formed mediator increases blood flow and vascular permeability, as well as stimulates the release of molecules from endothelial cell Weibel-Palade bodies (WPB), contributing to the activation of neighboring cells [177-179].
Prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT) are other types of mediators that, in addition to being involved in vasodilation and coagulation as histamine and WPB molecules, also participate in the generation of fever and leukocyte chemotaxis; these mediators are generated from arachidonic acid (AA) by the action of cyclooxygenase-2 (COX-2), in case of PG and TX; or 5-lipoxygenase (5-LOX), in case of LT [180].
Like the AA-derived mediators, the reactive oxygen species (ROS) are generated by enzymatic reactions of several enzymes, such as the NADPH oxidases (NOX). Although the most known function of ROS in the immune response is their involvement in the respiratory burst of the phagocytic process, ROS also perform other functions. Among these are the induction of vascular permeability by stimulating the enzymes phospholipase D (PLD) and phosphatase type 2A (PP2A) [181-183]; and the activation of several signal pathways; indeed, ROS signaling can activate the transcriptional factors NF-kB and hypoxia-inducible factor 1 (HIF-1) to drive the synthesis cytokines and cellular metabolic adaptations, respectively [184-190].
The most noticeable transcriptionally induced mediators in inflammation are cytokines and chemokines, such as interleukin (IL)-1p and IL-8. These are induced by different stimuli such as the mentioned ROS and PAMPs; these mediators can act in an autocrine, paracrine, and endocrine manner in different cells; for example, in APC could promote their migration, antigen processing capacity, expression of co-stimulatory molecules, and even the production of other cytokines [191-193].
On the other hand, once the dangerous stimuli are eliminated, the mediators of the onset phase are no longer produced or are counteracted by others, giving rise to the resolution phase. During this, the vascular tone is recovered, necrotic and apoptotic cells are eliminated, and the tissue is repaired [194].
Nitric oxide (NO) is an enzymatically produced mediator with anti-inflammatory properties; especially, NO produced by the endothelial nitric oxide synthase (eNOS) regulates the vascular tone and inhibits leukocyte migration [195]. Lipoxins, resolvins, protectins, and maresins are lipid-derived mediators that also limit leukocyte migration; moreover, these also limit ROS production and pro-inflammatory cytokines production and promote phagocytosis of apoptotic cells and the production of anti-inflammatory cytokines [196, 197].
Modulating cytokines of the onset phase involve their negative feedback and the production of anti-inflammatory ones [198]. A20 is a ubiquitin-editing enzyme induced as a negative regulator of pro-inflammatory cytokines signal, this functions as an upstream negative regulator of NF-kB, thus limiting pro-inflammatory cytokines production [199]. On the other hand, anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta (TGF-P) also are produced to shape the response of epithelial cells, fibroblasts, macrophages, and other cells during tissue repair [194, 200, 201].
Some respiratory viruses subvert the inflammatory process leading to pathological consequences. For example, it has been demonstrated that SARS CoV-2 takes advantage of histamine recognition by its H2 receptors on endothelial cells to increase its entry to them [202]. Also, in patients with severe COVID-19, it has been reported that in blood leukocytes, there is ROS overproduction, as well as the expression of its related transcriptional factor HIF-1a [203, 204]; it has even shown in vitro that HIF-1a facilitates SARS CoV-2 infection and other respiratory viruses [204, 205].
As SARS-CoV-2, severe influenza infections also have been reported to develop a hyper- inflammatory state in which oxidative stress and the expression of TNF-a, IL-10, and IFN-I and their related genes coexist simultaneously [206-211].
Several micronutrients participate in the modulation of the inflammatory response in different types of cells, mainly to avoid harmful effects due to its overactivation (Fig. 7).
Vitamin C has been recognized to modulate the inflammatory response directly by scavenging ROS or indirectly by inhibiting ROS-triggered signaling pathways. Its administration has been reported to diminish tissue damage and lower several pro- inflammatory mediators in lung injury induced by lipopolysaccharide (LPS] and influenza virus infection [212, 213]. In vitro, endothelial cells treated with 500pM of vitamin C have been shown to reverse LPS- and IFNy-induced vascular dysfunction [183], probably due to its function as a stabilizer of the tetrahydrobiopterin (BH4], a cofactor of the eNOS required for its proper function [214, 215]. However, it is essential to note that higher doses of

Fig. 7. modulate the inflammatory response

Micronutrients modulate the inflammatory response. Vitamin A (Vit. A) inhibits the nuclear factor kappa B (NF-kB) in macrophages. Vitamin D (Vit. D) induces the expression of several negative regulators of NF-kB and mitogen-activated protein kinases (MAPK), such as the inhibitory kappa B alpha (IkBoc),
MAPK phosphatase-1 (MKP-1), dual-specificity phosphatase 1 (DUSP1), thioesterase superfamily member 4 (THEM4), and T-cell Immunoglobulin 3 (TIM-3); as well promotes the function of the inhibitor of the nuclear factor-kB kinase (IKK) in macrophages. Zinc (Zn) is necessary to function the anti-inflammatory protein A20 in macrophages. Vitamin E (Vit. E) increases A20 levels through the dihydroceramide (DHC)/endoplasmic reticulum (ER) stress axis in macrophages, inhibits 5-lipoxygenase (5-LOX) activity in neutrophils, and decreases cyclooxygenase-2 (COX-2), NF-kB and mitogen- activated protein kinase (MAPK) activation in endothelial cells. Vitamin C (Vit. C) scavenges reactive oxygen species (ROS), stabilizes tetrahydrobiopterin (BH4), a cofactor of the endothelial nitric oxide synthase (eNOS); and promotes proteasomal degradation of hypoxia-inducible factor 1 (HIF-1) in endothelial cells. Figure created with BioRender.com.
vitamin C (3-10 mM) have been reported to have the opposite effect on endothelial cells [216], taking into account that 28-100uM are the serum physiological levels [217]. In addition, vitamin C has been reported to negatively regulate the transcriptional factors NF-kB and hypoxia-inducible factor 1 (HIF-1) [218]. However, this could be the effect of its antioxidant functions, for HIF-1 regulation could also be involved in its proteolytic degradation by the HIF-prolyl hydroxylase (HPHD), a type of aKGD which requires this vitamin as a cofactor [219].
Vitamin A seems to be a dual modulator of inflammation. In vitro anti-inflammatory functions have been reported in LPS-stimulated macrophages, in which RA doses from 10 to 100 mM diminish NF-kB activity. Conversely, in macrophages stimulated with different pro-inflammatory stimuli, the addition of lower concentrations ranging from 10 nM to 1 mM has shown the opposite effect, enhancing NF-kB activity, increasing IL-1P production, and inducing a metabolic shift [220, 221]. On the other hand, the anti-inflammatory effects of this vitamin have been observed in a sepsis model in mice, decreasing NF-kB target genes expression [222-224]; also, during parainfluenza virus infection in guinea pigs, RA treatment has been reported to diminish leukocyte infiltration and promote the expression of muscarinic receptors in the lungs improving their function [225]. Although these findings could seem contradictory, a possible explanation is that RA could exert different functions depending on concentration and the presence of another stimulus in the cellular environment.
Vitamin D negatively regulates the inflammatory response through different mechanisms, mainly in monocytes and macrophages. This vitamin could exert its functions through genetic expression induced by the VDR or physical interaction with other proteins. VDR has been reported to upregulate the expression of the inhibitory kappa B alpha (IkBœ), MAPK phosphatase-1 (MKP-1), dual-specificity phosphatase 1 (DUSP1), and thioesterase superfamily member 4 (THEM4) which are negative regulators of NF-kB and MAPK, thus limiting the pro-inflammatory response [92, 226-229]. VDR also has been shown to promote the expression of the T-cell Immunoglobulin 3 (TIM-3) in macrophages, a molecule involved in the acquisition of the M2 phenotype, which is required in the resolution of inflammation phase [230]; moreover, it has been described that VDR has other target genes with immunomodulatory functions in monocytes [49]. VDR also has been demonstrated to interact with the inhibitor of the nuclear factor-kB kinase (IKK), thus avoiding the NF-kB pro-inflammatory activity [231, 232]. Such is the relevance of immunomodulatory functions of this vitamin that it has been proposed as a treatment for airway inflammation in asthma [233], COPD [234], convalescent COVID-19 patients [235], and even as a preventive therapy for acute respiratory infections [236, 237].
Vitamin E also modulates the inflammatory response since it has been reported that during an LPS-induced acute airway inflammation model in mice, the a-tocopherol administration diminishes neutrophil infiltration to the lungs and reduces tissue damage [238]. Similarly, in vitro, it has been shown that lung epithelial cells under inflammatory conditions treated with a-tocopherol reduce IL-8 and adhesion molecule levels due to decreased NF-kB and MAPK activity [93]. Although these effects could be by the directly scavenging of ROS induced during inflammation, vitamin E could also act at different levels, as has been reported for y-tocopherol, ô-tocopherol, and some carboxychromanol metabolites that inhibit the COX-2-dependent prostaglandin E2 (PGE2) production in lung epithelial cells; or the carboxychromanol metabolites and y-tocopherol that inhibit LOX-5-dependent leukotriene B4 (LTB4) production in neutrophils and eosinophils [37, 38]. Tocotrienols y and ô have also been reported to regulate inflammatory response promoting the expression of A20 in macrophages through dihydroceramide (DHC) induction in the endoplasmic reticulum [239-241].
As mentioned, A20 is a negative regulator of NF-kB that requires zinc for its function [242]; indeed, in activated macrophages, zinc supplementation has been demonstrated to induce the expression of A20 while decreasing the activity of NF-kB resulting in lower expression of TNF-a and IL-1P [243]. Another mechanism that has been reported in which zinc regulates the inflammatory response is through the inhibition of phosphodiesterase function (PDE], leading to increased intracellular levels of cyclic guanosine monophosphate (cGMP] and the consequent protein kinase A (PKA] activation [244, 245], a kinase involved in negative regulation of NF-kB [246]. Additionally, zinc has been demonstrated to be required for superoxide dismutase (SOD] function [50], a zinc-dependent antioxidant enzyme relevant to lung damage limitation [247].
The role of magnesium during the inflammatory response was described more than twenty years ago in an LPS-induced sepsis model in rats with a deficient magnesium diet, showing a hyperinflammatory state and increased mortality [248]. In vitro, it has been reported that magnesium decreases the expression of IL-6 and TNF-a in LPS-stimulated monocytes; moreover, in acute lung injury in mice, magnesium treatment increases antioxidant response and reduces inflammatory cytokines through NF-kB inhibition [249]. Although the exact mechanism is not fully understood yet, one possible mechanism may be the antagonism between magnesium and calcium, as calcium depletion has been shown to replicate the anti-inflammatory effects of magnesium in vitro and in vivo [250, 251].

Roles in the adaptive cellular response

Specific cellular response against viruses involves processing endogenous antigens and the consequent loading of their derived peptides onto MHC-I molecules. Although all nucleated cells can carry out this process, for the initiation of the adaptive cellular response, this must be carried out by APC that present the antigenic peptides to a TCR of a specific Tc CD8+ lymphocyte. Upon TCR activation, co-stimulatory signals and cytokines are required to complete the activation of the Tc CD8+ lymphocytes to induce their clonal proliferation. Almost all Tc CD8+ lymphocytes have effector functions; however, a pool of memory cells is generated for future encounters with the antigen [252].
Effector Tc CD8+ lymphocytes, through their TCR, detect MHC-I molecules with the antigenic peptide of the infected cells. Once recognized, Tc CD8+ lymphocytes kill infected cells by expressing death ligands or releasing perforins and granzyme B. Tc CD8+ lymphocytes also could produce cytokines such as IFN-y and TNF-a, which are relevant for the autocrine stimulation and reinforcement of immunological memory [252-255]. To avoid an excessive response that could drive pathologic consequences, a late phase of contraction is necessary for which the majority of Tc CD8+ effector lymphocytes die, but a small portion becomes memory cells; this process requires the restriction of IL-2 production and the production of immunomodulatory cytokines derived from T regulatory (Treg) lymphocytes [255-258].
Some viruses such as metapneumovirus, influenza, and SARS-CoV-2 have been reported to alter Tc CD8+ lymphocytes response, resembling an exhaustion phenotype that impairs effector and memory functions, predisposing to delayed viral clearance and reinfections [155, 259-261].
In addition, influenza virus and SARS-CoV-2 have been reported to downregulate MHC-I expression in infected epithelial cells [149, 150]; therefore, even if Tc CD8+ lymphocytes were generated, they could not effectively recognize infected cells.
Many micronutrients support the adaptive cellular immune response since antigen presentation to Tc CD8+ lymphocyte effector functions (Fig. 8).
Vitamin A, as mentioned above, acts through the RAR, which is highly expressed in mature Tc CD8+ lymphocytes and plays a critical role in their function. It has been reported that the genetic ablation of the RARy isoform in hematopoietic cells results in low IFNy production, impaired cytotoxic function, and decreased proliferation of Tc CD8+ lymphocytes without compromising their development; however, RARy deletion also affects cytokine production of macrophages [262]. Moreover, the specific deletion of RARa isoform, but not RARy, in Tc CD8+ lymphocytes also has been shown to decrease the percentage of IL-2-producer and lower levels of the integrin a407 and chemokine receptor CCR9 [263], molecules required for T cells mucosal migration. This evidence suggests that RARa acts directly on Tc CD8+ lymphocyte function, whereas RARy could act indirectly via other cells, such as APC. In addition, since it has been reported that there is a RARE in the second intron of the MHC-I

Fig. 8. adaptive cellular response.

Micronutrients functions in adaptive cellular response. Vitamin A (Vit. A) acts on dendritic cells (DC), increasing major histocompatibility complex (MHC)- I molecules; on T cytotoxic (Tc)
CD8+ lymphocytes induce the expression of migration-associated molecules such as the C-C motif chemokine receptor 9 (CCR9) and the integrin a4?7: also promotes cytotoxicity, IL-2, and interferongamma (IFN) y production; in addition, stimulates memory cell.
Vitamin C (Vit. C) stimulates IL-12 production on DC. Vitamin D (Vit. D) participates in the T cell receptor (TCR) repertoire generation and could revert the exhausted phenotype on Tc CD8+ lymphocytes. Magnesium (Mg) stimulates the expression of the activator molecules CD25 and CD69; it is also necessary to activate leukocyte function-associated antigen 1 (LFA-1). Zinc (Zn) regulates the transcriptional factors for Tc CD8+ lymphocyte differentiation since it is required for the negative regulators Myc-associated zinc finger-related factor (MARZ) and zinc finger E-Box binding homeobox 2 (Zeb2), and the positive regulator Ikaros. In mature Tc CD8+ lymphocytes, Ikaros also inhibits cell activation. Figure created with BioRender.com.

gene in different species [264], vitamin A could increase MHC-I expression. Vitamin A also has been demonstrated to serve as an excellent adjuvant for vaccines, enhancing memory Tc CD8+ lymphocyte population with a more significant proliferative potential, as has been reported in a viral vector vaccination to lymphocytic choriomeningitis virus (LCV) glycoprotein in mice [265].
Vitamin D signaling also is necessary for proper T CD8+ lymphocytes function since it has been observed that genetic ablation of VDR in mice reduces their TCR repertoire, decreases granzyme B levels, and retains them in lymph nodes, affecting both their effector and memory functions [266]. In vitro, the treatment with vitamin D has been reported to revert the exhausted phenotype of blood-derived Tc CD8+ lymphocytes from lung cancer patients, and even its oral administration shows similar results [267]; suggesting that the beneficial effects of this vitamin in respiratory viral infections that promote an exhausted phenotype could be due in part to this same mechanism.
Since IL-12 expression, a cytokine required for T lymphocytes proliferation, involves the action of the Jumonji-C domain-containing histone demethylases (JHDM), a type of aKGD [268, 269], vitamin C could support the cellular response through the activity of this enzyme; indeed, this vitamin has been reported to enhance IL-12 production in APC [270, 271], that in turn results in an increased number of IFNY-producers Tc CD8+ lymphocytes [271]. Directly to Tc CD8+ lymphocytes, vitamin C has been shown to improve their cytotoxic function [272] and increase a memory phenotype, probably due to metabolic antioxidant adaptation [273].
Magnesium also has been demonstrated to participate in Tc CD8+ lymphocyte function since, in a mice model of influenza virus infection, a magnesium-deficient diet results in increased viral replication associated with decreased numbers of Tc CD8+ and Th CD4+ lymphocytes [274]; moreover, activated Tc CD8+ lymphocytes cultured in depleted magnesium medium have decreased proliferation capacity and reduced levels of the activation markers CD25 and CD69 both molecules required for T lymphocytes activation and proliferation [275]. In addition, extracellular magnesium has been reported to support the activation of the co-stimulatory molecule leukocyte function-associated antigen 1 (LFA- 1) in memory T CD8+ lymphocytes, a molecule necessary for the switch to a cytotoxic effector phenotype [276].
Finally, zinc participates in adaptive cellular response through the function of different zinc-finger transcriptional factors required for Tc CD8+ lymphocytes development and activation. It has been demonstrated that Myc-associated zinc finger-related factor (MARZ] and Zeb2 repress their differentiation, whereas Ikaros promotes it [277-279]; also, in mature Tc CD8+ lymphocytes, Ikaros has been reported to restrain Tc CD8+ lymphocytes activation [280].

Functions in the adaptive humoral response

This part of the response involves the processing and presentation of exogenous antigens, such as inactive viral particles or viral components contained in apoptotic bodies, onto MHC-II molecules to Th CD4+ lymphocytes. Also, co-stimulatory signals and cytokines are required for the complete activation of these cells. Once activated, Th CD4+ lymphocytes proliferate to become memory and effector cells that cooperate with B lymphocytes. Effector Th CD4+ lymphocytes could acquire different profiles driven by particular transcriptional factors; for example, T-bet drives to Th1, GATA-3 drives to Th2, the retinoid orphan receptor gamma t (RORyt) drives to Th17, and forkhead box P3 (FoxP3) drives to Treg; each profile is characterized besides their associated transcriptional factor, by the production of specific cytokines. Memory cells could remain in the SLO or become tissue memory cells. Lastly, for the B lymphocytes activation, BCR antigen recognition facilitated by the SLO’s follicular DC (FDC) and cooperation with the T CD4+ follicular helper (Tfh) lymphocytes occur to promote their activation and differentiation to antibodies-producer plasma cells (PC) as well as the generation of memory cells [281, 282].
During viral infections, the Th1 profile, characterized by IL-2, IFNy, and TNF-a production [283], has protective effects, as has been reported during SARS-CoV-2 and influenza infections [284, 285], in part due to its role in supporting the Tc CD8+ lymphocyte response [286]. Treg lymphocytes are also fundamental to controlling the overactivation of the Th1 and Tc CD8+ lymphocytes and aiding tissue repair once the infection is resolved [287, 288]. On the other hand, PC’s most relevant effector function to avoid viral infections at mucosal and systemic levels is the production of IgA and IgG antibody isotypes, as reported during SARS-CoV-2 and influenza infections [289-291]. These antibodies can neutralize viral particles or trigger the elimination of infected cells by their opsonization or antibody-dependent cell-mediated cytotoxicity (ADCC) [292].
A broad range of respiratory viruses alters lymphocytes response in different ways, such as causing lymphopenia that has been reported in SARS CoV-2, influenza virus, parainfluenza virus, and RSV infections [261, 293-296] or inducing a T lymphocyte exhaustion phenotype caused by SARS CoV-2 and influenza virus infections [261, 297]. Moreover, respiratory viruses also could subvert Th1/Th2 balance in different manners, leading to pathological consequences; for example, PBMC derived from RSV patients stimulated in vitro have been shown to impair IFNy and IL-2 production, both cytokines of Th1 profile; but able to produce IL-4, a cytokine of the Th2 profile [298, 299]. In contrast, rhinovirus infection, which is highly associated with the development of chronic obstructive pulmonary disease (COPD), has been shown to induce the production of Th1 cytokines but no Th2 cytokines in vitro [300]; and during metapneumovirus experimental infection, it has been demonstrated the convergence of Th1, Th2, and Th17 profiles [301]. In the case of severe SARS-CoV-2 infection in humans, there has been reported a marked increase in both Th1 and Th2 cytokines, contrary to pandemic H1N1 influenza infection, with a more discrete cytokine profile [302].
Regarding PC response, IgG antibody isotype is the most reported after immunizations and is related to protection and memory responses at the systemic level; however, in the case of respiratory viruses, mucosal IgA has been demonstrated to be more effective than IgG in serum, probably due to it resembles a natural infection [303-305]. Some viruses, such as RSV and SARS CoV-2, have been reported to impair IgA production [303, 306] or even to stimulate the IgE isotype switch, which is related to asthmatic complications, as has been demonstrated for RSV [307].
Several micronutrients regulate adaptive humoral response with a broad range of actions (Fig. 9).
Vitamin A functions on adaptive humoral response depending on the differentiation state of the cells. For example, the treatment of immature DC with vitamin A has been shown to induce apoptosis; conversely, in a mature phenotype under pro-inflammatory conditions stimulates the antigen-presentation capacity through the increased expression of MHC-II and co-stimulatory molecules although, under immunomodulatory conditions, enhances a tolerogenic phenotype [308-311]. In Th CD4+ lymphocytes, it has been shown that RARa is required for Th1 induction [312]; similarly to DC, vitamin A potentiates the Treg profile in immunomodulatory conditions by increasing FoxP3 expression, restricting, in both cases, the Th17 profile [313]. However, vitamin A has also been shown to support the Th2 profile [314, 315]. For the proper development of FDC, it has been reported that epithelial-derived RA is needed [316]; moreover, in mature FDC, RAR activation is necessary for the germinal center formation (GC) and in B lymphocytes to promote class switching to IgA isotype in the mucosa [317, 318]. However, the effects of vitamin A-derived RA on B lymphocytes seem to depend on their maturation stage since in common lymphoid progenitor cells (CLP) from mice embryos, RA has been shown to inhibit B cell differentiation, whereas in CLP from adult mice promote B cell differentiation [319]. In vivo, a RA-rich diet in mice has been demonstrated to promote B cell differentiation [320]; restricting the proliferation rate in stimulated mature B lymphocytes while increasing the activation-induced cytidine deaminase (AID) expression, a key enzyme for isotype class switch [321]. RA acid has also been reported to stimulate memory B cells proliferation and their differentiation to antibody-secreting PC [322].

Fig. 9. adaptive humoral response

Micronutrients functions in the adaptive humoral response. Vitamin A (Vit. A) induces apoptosis in immature dendritic cells (DC); whereas in mature DC increases major histocompatibility complex (MHC) II expression and, therefore, increases antigen presentation capacity; on T helper (Th) CD4+ lymphocytes, depending on the environment, could drive to Th1, or T regulatory (Treg) profile; on common lymphoid progenitor (CLP) and early lymphoid progenitor (ELP) stimulates B lymphocyte and plasma cell differentiation, and also promotes antibody class switching. Vitamin D (Vit. D] inhibits MHC-II expression on DC; increases the expression of the inhibitory molecules programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on Th CD4+ lymphocytes; stimulates antibody class switching on B lymphocytes, although it inhibits plasma cell differentiation. Vitamin C (Vit. C] stimulates MHC-II expression on DC; promotes Treg profile depending on environmental conditions; stimulates antibody class switching on B lymphocytes and their differentiation to plasma cells. Zinc (Zn) inhibits MHC-II expression on DC; promotes the Treg profile through the zinc- dependent transcriptional factors Ikaros, helios, and eos (solid lines); whereas it promotes Th1 by eos, and restricts it by Ikaros and aiolos (dotted lines); zinc could also modulate positively and negatively B lymphocyte differentiation. Magnesium (Mg) is necessary for the surface expression of the activating molecules CD25 and CD69 on Th CD4+ lymphocytes; it also stimulates B lymphocyte and plasma cell differentiation. Figure created with BioRender.com.

T-independent B lymphocyte response also could be protective against respiratory infections, such as those caused by influenza [323]; in this context, RAR also participates in T-independent B response promoting the localization of B lymphocytes in the marginal zone of secondary lymphoid organs (SLO], and the consequent production of IgM [324].
Vitamin D has an immunomodulatory effect on humoral response as described above for inflammatory response. In mature DC from mice, it has been reported that vitamin D treatment generates a tolerogenic profile characterized by reduced production of IL-12 and chemokines, decreased MHC-II and co-stimulatory molecules, and increased IL-10 production, which drives a reduced Th CD4+ lymphocyte proliferation [325, 326]. Directly on Th CD4+ lymphocytes, vitamin D also has been demonstrated to exert regulatory effects inducing the expression of the inhibitory surface markers programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4] [327]; molecules that drive contraction phase and Treg induction [327-329]. However, vitamin D has been shown to have the opposite effect under immunosuppressor conditions, increasing Th CD4+ lymphocyte numbers and IL-2 production [330]. Immunomodulatory effects of vitamin D also have been reported on B lymphocytes, reducing their proliferation and PC differentiation [331], regulating their APC function, and inducing the expression of IL-10 [332], suggesting that vitamin D modulates B activation, which could result in decreased antibody production. However, as occur with vitamin A, this effect seems to depend on the environmental conditions since vitamin D, in conjunction with vitamin A through VDR/RARa axis, sustains TGFp expression to induce isotype change to IgA [333].
Vitamin C has been reported to activate p38 MAPK on DC, leading to increased costimulatory and MHC-II surface levels [270, 334]; moreover, LPS-stimulated DC increases IL-12 production, driving a Th1 profile. However, as with other micronutrients, the effect of vitamin C depends on the environment since this vitamin has been reported to drive Th17 or Treg profiles by activating JHDM and TET demethylases, respectively [335-337]. On activated B lymphocytes, vitamin C has been shown to promote the differentiation to antibody-producing PC in vitro and in vivo through TET demethylases [338, 339]. In addition, vitamin C seems to promote isotype switching to IgG2 in vitro, although contradictory results have been found in vivo [340]; whatever the case, vitamin C appears to reinforce antibody production, as has been reported in patients infected with the SARS-CoV-2, in which oral supplementation for 42 days with vitamin C and zinc increase the levels of neutralizing antibodies [341].
Due to the broad range of proteins that require zinc for their function, this micronutrient act positively and negatively at different levels of the humoral response. In DC, it has been reported that zinc reduces MHC-II molecules’ surface levels and induces a tolerogenic phenotype, probably through the action of the anti-inflammatory zinc-dependent A20 protein [342, 343]. Interestingly, it has been reported that intracellular zinc is highly enriched in Treg lymphocytes compared to Th1 lymphocytes, and its depletion reverts the Treg profile leading to increased IFNy production [344]. Other zinc-dependent proteins, mainly transcriptional factors, dictate each Th profile in addition to their respective master transcription factors. For example, the Th1 profile is promoted by Eos and inhibited by Ikaros and Aiolos, whereas the Treg profile is promoted by Ikaros, Helios, and Eos [345]. In B lymphocytes, zinc is required during development, activation, and PC differentiation since it has been reported that during B cell development in mice, zinc uptake by the transporter ZIP10 is necessary during the transition of pro-B to pre-B lymphocyte stage, whereas ZIP7 is necessary during the transition of pre-B to immature-B lymphocyte stage [346, 347]. Also, the early B cell factor (EBF], the ATM Chk2-interacting zinc finger protein (ASCIZ], the zinc finger X-chromosomal protein (Zfx], and the Myc interacting zinc finger protein 1 (Miz-1] are zinc-dependent transcriptional factors that have been reported to promote the process [348351]. In contrast, the zinc-finger protein 521 (ZNF521] has been reported to regulate B cell development negatively [352]. During B lymphocyte activation, it has been reported that zinc uptake by ZnT7, ZIP7, ZIP9, and ZIP10 transporters is required [346, 353-355], leading to increased intracellular zinc levels that activate the B cell lymphoma 6 (Bcl-6) and leukemia/ lymphoma-related factor (LRF], molecules required for B lymphocytes proliferation [356358]. Finally, during PC differentiation, the zinc finger and BTB domain (ZBTB]20 and the B-lymphocyte-induced maturation protein 1 (Blimp-1] have been reported to activate them, whereas the ZTBT18 negatively regulated their differentiation [359-361].
Magnesium, similar that zinc, interacts with a broad range of proteins; however, there is little information about its participation in the humoral response. Magnesium has been reported to be necessary for proper T lymphocyte activation since its depletion reduces Tc CD8+ and Th CD4+ lymphocytes numbers in response to antigenic stimulation in vivo; also, in vitro affects the TCR-induced signal pathway, reducing CD69 and CD25 activation molecules and decreasing intracellular calcium flux in stimulated T lymphocytes, signals highly relevant for lymphocytes proliferation [275, 362]. In B lymphocytes, the uptake of this micronutrient through TRPM7 has been demonstrated to be required for their proper development since its deletion causes cell arrest in the pre-B lymphocyte stage [363]. In contrast, the deficiency of MAGT1 has been shown to cause an increase in mature B lymphocytes and reduced PC numbers [364], suggesting that magnesium uptake by MAGT regulates the transition of activated B lymphocytes to PC differentiation.

Concluding remarks

The statement that micronutrients help improve the immune system has been proven by a significant number of scientific evidence; however, the mechanisms of action do not consistently boost effector functions of the immune system; instead, micronutrients function by modulating each step of the immune response at the molecular level. For example, vitamin A seems to boost immune response and even has been proposed as a vaccine adjuvant [365]; conversely, vitamin D, in general, appears to have immunomodulatory effects in almost all phases of the immune response, being an excellent candidate for treating hyperinflammatory conditions, such as severe SARS-CoV-2 [366]. In addition, knowing the patient clinical condition plays a central role in considering if the supplementation with some micronutrients alone or in combination is helpful in its therapeutical management, taking into account that some of these micronutrients could possess antagonism or synergistic effects.

Acknowledgements
Author Contributions
A.P.J.U., conceptualization, literature searching, manuscript preparation; A.O.H., literature searching; Y.A.H, literature searching; J.P.C., conceptualization, manuscript revision, funding.
Funding
This research was funded by Consejo Nacional de Ciencia y Tecnología (CONACYT) México, Grants Numbers A1-S-7495; by Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT), Grant Number IN200922 of the Universidad Nacional Autónoma de México (UNAM); by Programa de Apoyo a la Investigación y el Posgrado (PAIP), Grant Number 5000-9105.

References

  1. Gu X, Zhou F, Wang Y, Fan G, Cao B: Respiratory viral sepsis: epidemiology, pathophysiology, diagnosis and treatment. Eur Respir Rev 2020;29:200038.
  2. Moriyama M, Hugentobler WJ, Iwasaki A: Seasonality of Respiratory Viral Infections. Annu Rev Virol 2020;7:83-101.
  3. Mettelman RC, Allen EK, Thomas PG: Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 2022;55:749-780.
  4. Kikkert M: Innate Immune Evasion by Human Respiratory RNA Viruses. J Innate Immun 2020;12:4-20.
  5. Dhabhar FS: Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 2014;58:193-210.
  6. Glencross DA, Ho TR, Camina N, Hawrylowicz CM, Pfeffer PE: Air pollution and its effects on the immune system. Free Radic Biol Med 2020;151:56-68.
  7. Klein SL, Flanagan KL: Sex differences in immune responses. Nat Rev Immunol 2016;16:626-638.
  8. Kreutmair S, Kauffmann M, Unger S, Ingelfinger F, Nunez NG, Alberti C, De Feo D, Krishnarajah S, Friebel E, Ulutekin C, Babaei S, Gaborit B, Lutz M, Jurado NP, Malek NP, Gopel S, Rosenberger P, Haberle HA, Ayoub I, Al-Hajj S, et al.: Preexisting comorbidities shape the immune response associated with severe COVID-19. J Allergy Clin Immunol 2022;150:312-324.
  9. Nobs SP, Zmora N, Elinav E: Nutrition Regulates Innate Immunity in Health and Disease. Annu Rev Nutr 2020;40:189-219.
  10. Calder PC: Feeding the immune system. Proc Nutr Soc 2013;72:299-309.
  11. Sanyaolu A, Okorie C, Marinkovic A, Patidar R, Younis K, Desai P, Hosein Z, Padda I, Mangat J, Altaf M: Comorbidity and its Impact on Patients with COVID-19. SN Compr Clin Med 2020:2:1069-1076.
  12. Wang X, Li X, Jin C, Bai X, Qi X, Wang J, Zhang L, Li N, Jin N, Song W, Gao H, Gao B, Zhang Y, Wang L: Association Between Serum Vitamin A Levels and Recurrent Respiratory Tract Infections in Children. Front Pediatr 2021;9:756217.
  13. Zhang X, Ding F, Li H, Zhao W, Jing H, Yan Y, Chen Y: Low Serum Levels of Vitamins A, D, and E Are Associated with Recurrent Respiratory Tract Infections in Children Living in Northern China: A Case Control Study. PLoS One 2016;11:e0167689.
  14. Qi YJ, Niu QL, Zhu XL, Zhao XZ, Yang WW, Wang XJ: Relationship between deficiencies in Vitamin A and E and occurrence of infectious diseases among children. Eur Rev Med Pharmacol Sci 2016;20:5009-5012.
  15. McNally JD, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM: Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol 2009;44:981-988.
  16. Karatekin G, Kaya A, Salihoglu O, Balci H, Nuhoglu A: Association of subclinical Vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr 2009;63:473-477.
  17. Kuwabara A, Tsugawa N, Ao M, Ohta J, Tanaka K: Vitamin D deficiency as the risk of respiratory tract infections in the institutionalized elderly: A prospective 1-year cohort study. Clin Nutr ESPEN 2020;40:309- 313.
  18. Myint PK, Wilson AM, Clark AB, Luben RN, Wareham NJ, Khaw KT: Plasma Vitamin C concentrations and risk of incident respiratory diseases and mortality in the European Prospective Investigation into CancerNorfolk population-based cohort study. Eur J Clin Nutr 2019;73:1492-1500.
  19. Khera D, Singh S, Purohit P, Sharma P, Singh K: Prevalence of Zinc Deficiency and the Effect of Zinc Supplementation on the Prevention of Acute Respiratory Infections. Turk Thorac J 2020;21:371-376.
  20. Nasser R, Naffaa ME, Mashiach T, Azzam ZS, Braun E: The association between serum Magnesium levels and community-acquired pneumonia 30-day mortality. BMC Infect Dis 2018;18:698.
  21. Pecora F, Persico F, Argentiero A, Neglia C, Esposito S: The Role of Micronutrients in Support of the Immune Response against Viral Infections. Nutrients 2020;12:3198.
  22. Junaid K, Ejaz H, Abdalla AE, Abosalif KOA, Ullah MI, Yasmeen H, Younas S, Hamam SSM, Rehman A: Effective Immune Functions of Micronutrients against SARS-CoV-2. Nutrients 2020;12:2992.
  23. Fernandes IG, de Brito CA, Dos Reis VMS, Sato MN, Pereira NZ: SARS-CoV-2 and Other Respiratory Viruses: What Does Oxidative Stress Have to Do with It? Oxid Med Cell Longev 2020;2020:8844280.
  24. Li Y, Schellhorn HE: New developments and novel therapeutic perspectives for Vitamin C. J Nutr 2007;137:2171-2184.
  25. Liu J, Hong J, Han H, Park J, Kim D, Park H, Ko M, Koh Y, Shin DY, Yoon SS: Decreased Vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration. Br J Cancer 2020;122:1445-1452.
  26. Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM, Cowin BL, Bruner E, Murphy MM, Chen W, Spangrude GJ, Hu Z, DeBerardinis RJ, Morrison SJ: Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 2017;549:476-481.
  27. Hong JM, Kim JH, Kang JS, Lee WJ, Hwang YI: Vitamin C is taken up by human T cells via sodium-dependent Vitamin C transporter 2 (SVCT2) and exerts inhibitory effects on the activation of these cells in vitro. Anat Cell Biol 2016;49:88-98.
  28. Padayatty SJ, Levine M: Vitamin C: the known and the unknown and Goldilocks. Oral Dis 2016;22:463-493.
  29. Levine M, Padayatty SJ, Espey MG: Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2011;2:78-88.
  30. Monfort A, Wutz A: Breathing-in epigenetic change with Vitamin C. EMBO Rep 2013;14:337-346.
  31. Schmolz L, Birringer M, Lorkowski S, Wallert M: Complexity of Vitamin E metabolism. World J Biol Chem 2016;7:14-43.
  32. Schubert M, Kluge S, Schmolz L, Wallert M, Galli F, Birringer M, Lorkowski S: Long-Chain Metabolites of Vitamin E: Metabolic Activation as a General Concept for Lipid-Soluble Vitamins? Antioxidants 2018;7:10.
  33. Goncalves A, Roi S, Nowicki M, Niot I, Reboul E: Cluster-determinant 36 (CD36) impacts on Vitamin E postprandial response. Mol Nutr Food Res 2014;58:2297-2306.
  34. Cooper GE, Pounce ZC, Wallington JC, Bastidas-Legarda LY, Nicholas B, Chidomere C, Robinson EC, Martin K, Tocheva AS, Christodoulides M, Djukanovic R, Wilkinson TM, Staples KJ: Viral Inhibition of Bacterial Phagocytosis by Human Macrophages: Redundant Role of CD36. PLoS One 2016;11:e0163889.
  35. Wang J, Nikrad MP, Travanty EA, Zhou B, Phang T, Gao B, Alford T, Ito Y, Nahreini P, Hartshorn K, Wentworth D, Dinarello CA, Mason RJ: Innate immune response of human alveolar macrophages during influenza A infection. PLoS One 2012;7:e29879.
  36. Bradford A, Atkinson J, Fuller N, Rand RP: The effect of Vitamin E on the structure of membrane lipid assemblies. J Lipid Res 2003;44:1940-1945.
  37. Jiang Z, Yin X, Jiang Q: Natural forms of Vitamin E and 13'-carboxychromanol, a long-chain Vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. J Immunol 2011;186:1173-1179.
  38. Jiang Q, Yin X, Lill MA, Danielson ML, Freiser H, Huang J: Long-chain carboxychromanols, metabolites of Vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci U S A 2008;105:20464-20469.
  39. Quinn PJ: Molecular associations of Vitamin E. Vitam Horm 2007;76:67-98.
  40. Landes N, Pfluger P, Kluth D, Birringer M, Ruhl R, Bol GF, Glatt H, Brigelius-Flohe R: Vitamin E activates gene expression via the pregnane X receptor. Biochem Pharmacol 2003;65:269-273.
  41. Ghyselinck NB, Duester G: Retinoic acid signaling pathways. Development 2019;146:dev167502.
  42. Kelly M, von Lintig J: STRA6: role in cellular retinol uptake and efflux. Hepatobiliary Surg Nutr 2015;4:229- 242.
  43. Lee KH, Chang MY, Ahn JI, Yu DH, Jung SS, Choi JH, Noh YH, Lee YS, Ahn MJ: Differential gene expression in retinoic acid-induced differentiation of acute promyelocytic leukemia cells, NB4 and HL-60 cells. Biochem Biophys Res Commun 2002;296:1125-1133.
  44. Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ, Tong JH, Lanotte M, Waxman S, Chen SJ, Mao M, Hu GX, Zhu L, Chen Z: Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 2000;96:1496-1504.
  45. Kundu R, Chain BM, Coussens AK, Khoo B, Noursadeghi M: Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell-autonomous activation of Vitamin D in dendritic cells. Eur J Immunol 2014;44:1781-1790.
  46. Lopez DV, Al-Jaberi FAH, Woetmann A, Odum N, Bonefeld CM, Kongsbak-Wismann M, Geisler C: Macrophages Control the Bioavailability of Vitamin D and Vitamin D-Regulated T Cell Responses. Front Immunol 2021;12:722806.
  47. Kongsbak M, von Essen MR, Boding L, Levring TB, Schjerling P, Lauritsen JP, Woetmann A, Odum N, Bonefeld CM, Geisler C: Vitamin D up-regulates the Vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells. PLoS One 2014;9:e96695.
  48. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G: Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev 2016;96:365-408.
  49. Koivisto O, Hanel A, Carlberg C: Key Vitamin D Target Genes with Functions in the Immune System. Nutrients 2020;12:1140.
  50. Ireland SM, Martin ACR: ZincBind-the database of Zinc binding sites. Database (Oxford) 2019;2019:baz006.
  51. Kaur K, Gupta R, Saraf SA, Saraf SK: Zinc: The Metal of Life. Compr Rev Food Sci Food Saf 2014;13:358-376.
  52. Maares M, Haase H: A Guide to Human Zinc Absorption: General Overview and Recent Advances of In vitro Intestinal Models. Nutrients 2020;12:762.
  53. Nodera M, Yanagisawa H, Wada O: Increased apoptosis in a variety of tissues of Zinc-deficient rats. Life Sci 2001;69:1639-1649.
  54. King LE, Frentzel JW, Mann JJ, Fraker PJ: Chronic Zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained. J Am Coll Nutr 2005;24:494- 502.
  55. Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW: Interleukin 1 regulates secretion of Zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C. Proc Natl Acad Sci U S A 1992;89:7752-7756.
  56. Saha AR, Hadden EM, Hadden JW: Zinc induces thymulin secretion from human thymic epithelial cells in vitro and augments splenocyte and thymocyte responses in vivo. Int J Immunopharmacol 1995;17:729-733.
  57. Fiorentini D, Cappadone C, Farruggia G, Prata C: Magnesium: Biochemistry, Nutrition, Detection, and Social Impact of Diseases Linked to Its Deficiency. Nutrients 2021;13:1136.
  58. Brandao K, Deason-Towne F, Perraud AL, Schmitz C: The role of Mg2+ in immune cells. Immunol Res 2013;55:261-269.
  59. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ: Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 2011;475:471-476.
  60. Lieleg O, Lieleg C, Bloom J, Buck CB, Ribbeck K: Mucin biopolymers as broad-spectrum antiviral agents. Biomacromolecules 2012;13:1724-1732.
  61. McAuley JL, Corcilius L, Tan HX, Payne RJ, McGuckin MA, Brown LE: The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunol 2017;10:1581-1593.
  62. Li Y, Dinwiddie DL, Harrod KS, Jiang Y, Kim KC: Anti-inflammatory effect of MUC1 during respiratory syncytial virus infection of lung epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 2010;298:L558- 563.
  63. Lu W, Liu X, Wang T, Liu F, Zhu A, Lin Y, Luo J, Ye F, He J, Zhao J, Li Y, Zhong N: Elevated MUC1 and MUC5AC mucin protein levels in airway mucus of critical ill COVID-19 patients. J Med Virol 2021;93:582-584.
  64. Jiang Y, Yang D, Li W, Wang B, Jiang Z, Li M: Antiviral activity of recombinant mouse beta-defensin 3 against influenza A virus in vitro and in vivo. Antivir Chem Chemother 2012;22:255-262.
  65. LeMessurier KS, Lin Y, McCullers JA, Samarasinghe AE: Antimicrobial peptides alter early immune response to influenza A virus infection in C57BL/6 mice. Antiviral Res 2016;133:208-217.
  66. Li W, Feng Y, Kuang Y, Zeng W, Yang Y, Li H, Jiang Z, Li M: Construction of eukaryotic expression vector with mBD1-mBD3 fusion genes and exploring its activity against influenza A virus. Viruses 2014;6:1237-1252.
  67. Kota S, Sabbah A, Chang TH, Harnack R, Xiang Y, Meng X, Bose S: Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus. J Biol Chem 2008;283:22417-22429.
  68. Zhao H, Zhou J, Zhang K, Chu H, Liu D, Poon VK, Chan CC, Leung HC, Fai N, Lin YP, Zhang AJ, Jin DY, Yuen KY, Zheng BJ: A novel peptide with potent and broad-spectrum antiviral activities against multiple respiratory viruses. Sci Rep 2016;6:22008.
  69. Kim J, Yang YL, Jang SH, Jang YS: Human beta-defensin 2 plays a regulatory role in innate antiviral immunity and is capable of potentiating the induction of antigen-specific immunity. Virol J 2018;15:124.
  70. Vemula SV, Amen O, Katz JM, Donis R, Sambhara S, Mittal SK: Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time. Virus Res 2013;178:398-403.
  71. Xu C, Wang A, Marin M, Honnen W, Ramasamy S, Porter E, Subbian S, Pinter A, Melikyan GB, Lu W, Chang TL: Human Defensins Inhibit SARS-CoV-2 Infection by Blocking Viral Entry. Viruses 2021;13:1246.
  72. Faurschou M, Sorensen OE, Johnsen AH, Askaa J, Borregaard N: Defensin-rich granules of human neutrophils: characterization of secretory properties. Biochim Biophys Acta 2002;1591:29-35.
  73. Abdeen S, Bdeir K, Abu-Fanne R, Maraga E, Higazi M, Khurram N, Feldman M, Deshpande C, Litzky LA, Heyman SN, Montone KT, Cines DB, Higazi AA: Alpha-defensins: risk factor for thrombosis in COVID-19 infection. Br J Haematol 2021;194:44-52.
  74. Currie SM, Gwyer Findlay E, McFarlane AJ, Fitch PM, Bottcher B, Colegrave N, Paras A, Jozwik A, Chiu C, Schwarze J, Davidson DJ: Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In vitro and Protective Function In vivo in Mice and Humans. J Immunol 2016;196:2699-2710.
  75. Harcourt JL, McDonald M, Svoboda P, Pohl J, Tatti K, Haynes LM: Human cathelicidin, LL-37, inhibits respiratory syncytial virus infection in polarized airway epithelial cells. BMC Res Notes 2016;9:11.
  76. Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL: The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol 2013;94:40-49.
  77. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, Davidson DJ, Donis RO: Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 2011;6:e25333.
  78. Sousa FH, Casanova V, Findlay F, Stevens C, Svoboda P, Pohl J, Proudfoot L, Barlow PG: Cathelicidins display conserved direct antiviral activity towards rhinovirus. Peptides 2017;95:76-83.
  79. Casanova V, Sousa FH, Shakamuri P, Svoboda P, Buch C, D'Acremont M, Christophorou MA, Pohl J, Stevens C, Barlow PG: Citrullination Alters the Antiviral and Immunomodulatory Activities of the Human Cathelicidin LL-37 During Rhinovirus Infection. Front Immunol 2020;11:85.
  80. Wang C, Wang S, Li D, Chen P, Han S, Zhao G, Chen Y, Zhao J, Xiong J, Qiu J, Wei DQ, Zhao J, Wang J: Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone. ACS Infect Dis 2021;7:1545- 1554.
  81. Marquez HA, Chen F: Retinoic Acid Signaling and Development of the Respiratory System. Subcell Biochem 2020;95:151-174.
  82. Niu C, Liu N, Liu J, Zhang M, Ying L, Wang L, Tian D, Dai J, Luo Z, Liu E, Zou L, Fu Z: Vitamin A maintains the airway epithelium in a murine model of asthma by suppressing glucocorticoid-induced leucine zipper. Clin Exp Allergy 2016;46:848-860.
  83. Liu J, Zhang M, Niu C, Luo Z, Dai J, Wang L, Liu E, Fu Z: Dexamethasone inhibits repair of human airway epithelial cells mediated by glucocorticoid-induced leucine zipper (GILZ). PLoS One 2013;8:e60705.
  84. Esteban-Pretel G, Marin MP, Renau-Piqueras J, Sado Y, Barber T, Timoneda J: Vitamin A deficiency disturbs collagen IV and laminin composition and decreases matrix metalloproteinase concentrations in rat lung. Partial reversibility by retinoic acid. J Nutr Biochem 2013;24:137-145.
  85. Koo JS, Jetten AM, Belloni P, Yoon JH, Kim YD, Nettesheim P: Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells. Biochem J 1999;338:351-357.
  86. Kim SW, Hong JS, Ryu SH, Chung WC, Yoon JH, Koo JS: Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway. Mol Cell Biol 2007;27:6933-6947.
  87. Jacobo-Delgado YM, Torres-Juarez F, Rodriguez-Carlos A, Santos-Mena A, Enciso-Moreno JE, Rivas-Santiago C, Diamond G, Rivas-Santiago B: Retinoic acid induces antimicrobial peptides and cytokines leading to Mycobacterium tuberculosis elimination in airway epithelial cells. Peptides 2021;142:170580.
  88. Schrumpf JA, Amatngalim GD, Veldkamp JB, Verhoosel RM, Ninaber DK, Ordonez SR, van der Does AM, Haagsman HP, Hiemstra PS: Proinflammatory Cytokines Impair Vitamin D-Induced Host Defense in Cultured Airway Epithelial Cells. Am J Respir Cell Mol Biol 2017;56:749-761.
  89. Brockman-Schneider RA, Pickles RJ, Gern JE: Effects of Vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS One 2014;9:e86755.
  90. Merriman KE, Kweh MF, Powell JL, Lippolis JD, Nelson CD: Multiple beta-defensin genes are upregulated by the Vitamin D pathway in cattle. J Steroid Biochem Mol Biol 2015;154:120-129.
  91. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH: Cutting edge: 1,25-dihydroxyVitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909-2912.
  92. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW: Respiratory epithelial cells convert inactive Vitamin D to its active form: potential effects on host defense. J Immunol 2008;181:7090- 7099.
  93. Ekstrand-Hammarstrom B, Osterlund C, Lilliehook B, Bucht A: Vitamin E down-modulates mitogen- activated protein kinases, nuclear factor-kappaB and inflammatory responses in lung epithelial cells. Clin Exp Immunol 2007;147:359-369.
  94. Feldman C, Anderson R, Theron AJ, Steel HC, van Rensburg CE, Cole PJ, Wilson R: Vitamin E attenuates the injurious effects of bioactive phospholipids on human ciliated epithelium in vitro. Eur Respir J 2001;18:122-129.
  95. Wang X, Nijman R, Camuzeaux S, Sands C, Jackson H, Kaforou M, Emonts M, Herberg JA, Maconochie I, Carrol ED, Paulus SC, Zenz W, Van der Flier M, de Groot R, Martinon-Torres F, Schlapbach LJ, Pollard AJ, Fink C, Kuijpers TT, Anderson S, et al.: Plasma lipid profiles discriminate bacterial from viral infection in febrile children. Sci Rep 2019;9:17714.
  96. Niewoehner DE, Rice K, Sinha AA, Wangensteen D: Injurious effects of lysophosphatidylcholine on barrier properties of alveolar epithelium. J Appl Physiol (1985) 1987;63:1979-1986.
  97. McManus LM, Deavers SI: Platelet activating factor in pulmonary pathobiology. Clin Chest Med 1989;10:107-118.
  98. Mereness JA, Bhattacharya S, Wang Q, Ren Y, Pryhuber GS, Mariani TJ: Type VI collagen promotes lung epithelial cell spreading and wound-closure. PLoS One 2018;13:e0209095.
  99. Liu C, Huang K, Li G, Wang P, Liu C, Guo C, Sun Z, Pan J: Ascorbic acid promotes 3T3-L1 cells adipogenesis by attenuating ERK signaling to upregulate the collagen VI. Nutr Metab (Lond) 2017;14:79.
  100. Fischer H, Schwarzer C, Illek B: Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel. Proc Natl Acad Sci U S A 2004;101:3691-3696.
  101. Adler KB, Tuvim MJ, Dickey BF: Regulated mucin secretion from airway epithelial cells. Front Endocrinol (Lausanne) 2013;4:129.
  102. Roscioli E, Jersmann HP, Lester S, Badiei A, Fon A, Zalewski P, Hodge S: Zinc deficiency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD. Int J Chron Obstruct Pulmon Dis 2017;12:3503-3510.
  103. Bao S, Knoell DL: Zinc modulates cytokine-induced lung epithelial cell barrier permeability. Am J Physiol Lung Cell Mol Physiol 2006;291:L1132-1141.
  104. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, et al.: A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-879.
  105. Anderson CS, Chu CY, Wang Q, Mereness JA, Ren Y, Donlon K, Bhattacharya S, Misra RS, Walsh EE, Pryhuber GS, Mariani TJ: CX3CR1 as a respiratory syncytial virus receptor in pediatric human lung. Pediatr Res 2020;87:862-867.
  106. Alymova IV, Portner A, Mishin VP, McCullers JA, Freiden P, Taylor GL: Receptor-binding specificity of the human parainfluenza virus type 1 hemagglutinin-neuraminidase glycoprotein. Glycobiology 2012;22:174- 180.
  107. Nicholls JM, Bourne AJ, Chen H, Guan Y, Peiris JS: Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses. Respir Res 2007;8:73.
  108. Baggen J, Thibaut HJ, Staring J, Jae LT, Liu Y, Guo H, Slager JJ, de Bruin JW, van Vliet AL, Blomen VA, Overduin P, Sheng J, de Haan CA, de Vries E, Meijer A, Rossmann MG, Brummelkamp TR, van Kuppeveld FJ: Enterovirus D68 receptor requirements unveiled by haploid genetics. Proc Natl Acad Sci U S A 2016;113:1399-1404.
  109. Cox RG, Mainou BA, Johnson M, Hastings AK, Schuster JE, Dermody TS, Williams JV: Human Metapneumovirus Is Capable of Entering Cells by Fusion with Endosomal Membranes. PLoS Pathog 2015;11:e1005303.
  110. Rankl C, Kienberger F, Wildling L, Wruss J, Gruber HJ, Blaas D, Hinterdorfer P: Multiple receptors involved in human rhinovirus attachment to live cells. Proc Natl Acad Sci U S A 2008;105:17778-17783.
  111. Hograindleur MA, Effantin G, Fenel D, Mas C, Lieber A, Schoehn G, Fender P, Vassal-Stermann E: Binding Mechanism Elucidation of the Acute Respiratory Disease Causing Agent Adenovirus of Serotype 7 to Desmoglein-2. Viruses 2020;12:1075.
  112. Bauernfried S, Scherr MJ, Pichlmair A, Duderstadt KE, Hornung V: Human NLRP1 is a sensor for double- stranded RNA. Science 2021;371:eabd0811.
  113. Zhu S, Ding S, Wang P, Wei Z, Pan W, Palm NW, Yang Y, Yu H, Li HB, Wang G, Lei X, de Zoete MR, Zhao J, Zheng Y, Chen H, Zhao Y, Jurado KA, Feng N, Shan L, Kluger Y, et al.: Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 2017;546:667-670.
  114. Li D, Wu M: Pattern recognition receptors in health and diseases. Signal transduction and targeted therapy 2021;6:291.
  115. Su C, Tang YD, Zheng C: DExD/H-box helicases: multifunctional regulators in antiviral innate immunity. Cell Mol Life Sci 2021;79:2.
  116. Chiang HS, Liu HM: The Molecular Basis of Viral Inhibition of IRF- and STAT-Dependent Immune Responses. Front Immunol 2018;9:3086.
  117. Liu T, Zhang L, Joo D, Sun SC: NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017;2:17023.
  118. Guan J, Miah SM, Wilson ZS, Erick TK, Banh C, Brossay L: Role of type I interferon receptor signaling on NK cell development and functions. PLoS One 2014;9:e111302.
  119. Madera S, Rapp M, Firth MA, Beilke JN, Lanier LL, Sun JC: Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J Exp Med 2016;213:225-233.
  120. Lee AJ, Mian F, Poznanski SM, Stackaruk M, Chan T, Chew MV, Ashkar AA: Type I Interferon Receptor on NK Cells Negatively Regulates Interferon-gamma Production. Front Immunol 2019;10:1261.
  121. Simmons DP, Wearsch PA, Canaday DH, Meyerson HJ, Liu YC, Wang Y, Boom WH, Harding CV: Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing. J Immunol 2012;188:3116-3126.
  122. Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP: Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 2014;12:e1001759.
  123. Lokugamage KG, Hage A, de Vries M, Valero-Jimenez AM, Schindewolf C, Dittmann M, Rajsbaum R, Menachery VD: Type I Interferon Susceptibility Distinguishes SARS-CoV-2 from SARS-CoV. J Virol 2020;94:e01410-20.
  124. Mibayashi M, Martinez-Sobrido L, Loo YM, Cardenas WB, Gale M, Jr., Garcia-Sastre A: Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 2007;81:514-524.
  125. Zhang W, Yang H, Kong X, Mohapatra S, San Juan-Vergara H, Hellermann G, Behera S, Singam R, Lockey RF, Mohapatra SS: Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med 2005;11:56-62.
  126. Ban J, Lee NR, Lee NJ, Lee JK, Quan FS, Inn KS: Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling. Viruses 2018;10:716.
  127. Kumar A, Ishida R, Strilets T, Cole J, Lopez-Orozco J, Fayad N, Felix-Lopez A, Elaish M, Evseev D, Magor KE, Mahal LK, Nagata LP, Evans DH, Hobman TC: SARS-CoV-2 Nonstructural Protein 1 Inhibits the Interferon Response by Causing Depletion of Key Host Signaling Factors. J Virol 2021;95:e0026621.
  128. Galani IE, Rovina N, Lampropoulou V, Triantafyllia V, Manioudaki M, Pavlos E, Koukaki E, Fragkou PC, Panou V, Rapti V, Koltsida O, Mentis A, Koulouris N, Tsiodras S, Koutsoukou A, Andreakos E: Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol 2021;22:32-40.
  129. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Pere H, Charbit B, Bondet V, Chenevier- Gobeaux C, Breillat P, Carlier N, Gauzit R, Morbieu C, Pene F, Marin N, Roche N, Szwebel TA, Merkling SH, Treluyer JM, et al.: Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718-724.
  130. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR: Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 Cell 2020;181:1036-1045 e1039.
  131. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, Perlman S: Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV- Infected Mice. Cell Host Microbe 2016;19:181-193.
  132. Soye KJ, Trottier C, Richardson CD, Ward BJ, Miller WH, Jr.: RIG-I is required for the inhibition of measles virus by retinoids. PLoS One 2011;6:e22323.
  133. Liu G, Park HS, Pyo HM, Liu Q, Zhou Y: Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction. J Virol 2015;89:6067-6079.
  134. Kouwaki T, Nishimura T, Wang G, Oshiumi H: RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses. Front Immunol 2021;12:700926.
  135. Goutagny N, Jiang Z, Tian J, Parroche P, Schickli J, Monks BG, Ulbrandt N, Ji H, Kiener PA, Coyle AJ, Fitzgerald KA: Cell type-specific recognition of human metapneumoviruses (HMPVs) by retinoic acid-inducible gene I (RIG-I) and TLR7 and viral interference of RIG-I ligand recognition by HMPV-B1 phosphoprotein. J Immunol 2010;184:1168-1179.
  136. Sabbah A, Bose S: Retinoic acid inducible gene I activates innate antiviral response against human parainfluenza virus type 3. Virol J 2009;6:200.
  137. Teafatiller T, Agrawal S, De Robles G, Rahmatpanah F, Subramanian VS, Agrawal A: Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells. Biomolecules 2021;11:1148.
  138. Verhelst J, Parthoens E, Schepens B, Fiers W, Saelens X: Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. J Virol 2012;86:13445- 13455.
  139. Verhelst J, Hulpiau P, Saelens X: Mx proteins: antiviral gatekeepers that restrain the uninvited. Microbiol Mol Biol Rev 2013;77:551-566.
  140. Fujisawa K, Hara K, Takami T, Okada S, Matsumoto T, Yamamoto N, Sakaida I: Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells. Stem Cell Res Ther 2018;9:93.
  141. Kc S, Carcamo JM, Golde DW: Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 2005;19:1657-1667.
  142. Cai Y, Li YF, Tang LP, Tsoi B, Chen M, Chen H, Chen XM, Tan RR, Kurihara H, He RR: A new mechanism of Vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. Biomed Res Int 2015;2015:675149.
  143. Wu B, Hur S: How RIG-I like receptors activate MAVS. Curr Opin Virol 2015;12:91-98.
  144. Berg K, Bolt G, Andersen H, Owen TC: Zinc potentiates the antiviral action of human IFN-alpha tenfold. J Interferon Cytokine Res 2001;21:471-474.
  145. Lian H, Wei J, Zang R, Ye W, Yang Q, Zhang XN, Chen YD, Fu YZ, Hu MM, Lei CQ, Luo WW, Li S, Shu HB:
  146. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response. Nat Commun 2018;9:3349.
  147. Lian H, Zang R, Wei J, Ye W, Hu MM, Chen YD, Zhang XN, Guo Y, Lei CQ, Yang Q, Luo WW, Li S, Shu HB: The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors. Immunity 2018;49:438-448 e435.
  148. Zang R, Lian H, Zhong X, Yang Q, Shu HB: ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3 J Mol Cell Biol 2020;12:251-262.
  149. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW: Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 2010;184:965-974.
  150. Koutsakos M, McWilliam HEG, Aktepe TE, Fritzlar S, Illing PT, Mifsud NA, Purcell AW, Rockman S, Reading PC, Vivian JP, Rossjohn J, Brooks AG, Mackenzie JM, Mintern JD, Villadangos JA, Nguyen THO, Kedzierska K: Downregulation of MHC Class I Expression by Influenza A and B Viruses. Front Immunol 2019;10:1158.
  151. Zhang Y, Chen Y, Li Y, Huang F, Luo B, Yuan Y, Xia B, Ma X, Yang T, Yu F, Liu J, Liu B, Song Z, Chen J, Yan S, Wu L, Pan T, Zhang X, Li R, Huang W, et al.: The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Iota. Proc Natl Acad Sci U S A 2021;118:e2024202118.
  152. Perera Molligoda Arachchige AS: Human NK cells: From development to effector functions. Innate Immun 2021;27:212-229.
  153. Chan CJ, Smyth MJ, Martinet L: Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ 2014;21:5-14.
  154. Vidal SM, Khakoo SI, Biron CA: Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol 2011;1:497-512.
  155. Diab M, Schmiedel D, Seidel E, Bacharach E, Mandelboim O: Human Metapneumovirus Escapes NK Cell Recognition through the Downregulation of Stress-Induced Ligands for NKG2D. Viruses 2020;12:781.
  156. Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, Xu Y, Tian Z: Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020;17:533-535.
  157. Poznanski SM, Ashkar AA: What Defines NK Cell Functional Fate: Phenotype or Metabolism? Front Immunol 2019;10:1414.
  158. Zhou G, Juang SW, Kane KP: NK cells exacerbate the pathology of influenza virus infection in mice. Eur J Immunol 2013;43:929-938.
  159. Li F, Zhu H, Sun R, Wei H, Tian Z: Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection. J Virol 2012;86:2251-2258.
  160. Harker JA, Godlee A, Wahlsten JL, Lee DC, Thorne LG, Sawant D, Tregoning JS, Caspi RR, Bukreyev A, Collins PL, Openshaw PJ: Interleukin 18 coexpression during respiratory syncytial virus infection results in enhanced disease mediated by natural killer cells. J Virol 2010;84:4073-4082.
  161. Li A, He M, Wang H, Qiao B, Chen P, Gu H, Zhang M, He S: All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92. Biochem Biophys Res Commun 2007;352:42-47.
  162. Dawson HD, Li NQ, DeCicco KL, Nibert JA, Ross AC: Chronic marginal Vitamin A status reduces natural killer cell number and function in aging Lewis rats. J Nutr 1999;129:1510-1517.
  163. Bowman TA, Goonewardene IM, Pasatiempo AM, Ross AC, Taylor CE: Vitamin A deficiency decreases natural killer cell activity and interferon production in rats. J Nutr 1990;120:1264-1273.
  164. Vassiliou AG, Jahaj E, Pratikaki M, Keskinidou C, Detsika M, Grigoriou E, Psarra K, Orfanos SE, Tsirogianni A, Dimopoulou I, Kotanidou A: Vitamin D deficiency correlates with a reduced number of natural killer cells in intensive care unit (ICU) and non-ICU patients with COVID-19 pneumonia. Hellenic J Cardiol 2021;62:381- 383.
  165. Lee KN, Kang HS, Jeon JH, Kim EM, Yoon SR, Song H, Lyu CY, Piao ZH, Kim SU, Han YH, Song SS, Lee YH, Song KS, Kim YM, Yu DY, Choi I: VDUP1 is required for the development of natural killer cells. Immunity 2005;22:195-208.
  166. Al-Jaderi Z, Maghazachi AA: Effects of Vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. Toxins (Basel) 2013;5:1932-1947.
  167. Lee GY, Park CY, Cha KS, Lee SE, Pae M, Han SN: Differential effect of dietary Vitamin D supplementation on natural killer cell activity in lean and obese mice. J Nutr Biochem 2018;55:178-184.
  168. Park CY, Han SN: The Role of Vitamin D in Adipose Tissue Biology: Adipocyte Differentiation, Energy Metabolism, and Inflammation. J Lipid Atheroscler 2021;10:130-144.
  169. Huijskens MJ, Walczak M, Sarkar S, Atrafi F, Senden-Gijsbers BL, Tilanus MG, Bos GM, Wieten L, Germeraad WT: Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015;17:613-620.
  170. Wu CY, Zhang B, Kim H, Anderson SK, Miller JS, Cichocki F: Ascorbic Acid Promotes KIR Demethylation during Early NK Cell Differentiation. J Immunol 2020;205:1513-1523.
  171. Muzzioli M, Stecconi R, Moresi R, Provinciali M: Zinc improves the development of human CD34+ cell progenitors towards NK cells and increases the expression of GATA-3 transcription factor in young and old ages. Biogerontology 2009;10:593-604.
  172. van Helden MJ, Goossens S, Daussy C, Mathieu AL, Faure F, Marcais A, Vandamme N, Farla N, Mayol K, Viel S, Degouve S, Debien E, Seuntjens E, Conidi A, Chaix J, Mangeot P, de Bernard S, Buffat L, Haigh JJ, Huylebroeck D, et al.: Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection. J Exp Med 2015;212:2015-2025.
  173. Samson SI, Richard O, Tavian M, Ranson T, Vosshenrich CA, Colucci F, Buer J, Grosveld F, Godin I, Di Santo JP: GATA-3 promotes maturation, IFN-gamma production, and liver-specific homing of NK cells. Immunity 2003;19:701-711.
  174. Kumar S, Rajagopalan S, Sarkar P, Dorward DW, Peterson ME, Liao HS, Guillermier C, Steinhauser ML, Vogel SS, Long EO: Zinc-Induced Polymerization of Killer-Cell Ig-like Receptor into Filaments Promotes Its Inhibitory Function at Cytotoxic Immunological Synapses. Mol Cell 2016;62:21-33.
  175. Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, et al.: Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 2013;341:186-191.
  176. Medzhitov R: The spectrum of inflammatory responses. Science 2021;374:1070-1075.
  177. Abdulkhaleq LA, Assi MA, Abdullah R, Zamri-Saad M, Taufiq-Yap YH, Hezmee MNM: The crucial roles of inflammatory mediators in inflammation: A review. Vet World 2018;11:627-635.
  178. Pober JS, Sessa WC: Inflammation and the blood microvascular system. Cold Spring Harb Perspect Biol 2014;7:a016345.
  179. Miteva KT, Pedicini L, Wilson LA, Jayasinghe I, Slip RG, Marszalek K, Gaunt HJ, Bartoli F, Deivasigamani S, Sobradillo D, Beech DJ, McKeown L: Rab46 integrates Ca(2+) and histamine signaling to regulate selective cargo release from Weibel-Palade bodies. J Cell Biol 2019;218:2232-2246.
  180. Holthenrich A, Drexler HCA, Chehab T, Nass J, Gerke V: Proximity proteomics of endothelial Weibel-Palade bodies identifies novel regulator of von Willebrand factor secretion. Blood 2019;134:979-982.
  181. Farooque SP, Arm JP, Lee TH: Lipid Mediators: Leukotrienes, Prostanoids, Lipoxins, and Platelet-Activating Factor; in: Allergy and Allergic Diseases, Blackwell Scientific, 2008, pp 566-633.
  182. Usatyuk PV, Kotha SR, Parinandi NL, Natarajan V: Phospholipase D signaling mediates reactive oxygen species-induced lung endothelial barrier dysfunction. Pulm Circ 2013;3:108-115.
  183. Patel RB, Kotha SR, Sherwani SI, Sliman SM, Gurney TO, Loar B, Butler SO, Morris AJ, Marsh CB, Parinandi NL: Pulmonary fibrosis inducer, bleomycin, causes redox-sensitive activation of phospholipase D and cytotoxicity through formation of bioactive lipid signal mediator, phosphatidic acid, in lung microvascular endothelial cells. Int J Toxicol 2011;30:69-90.
  184. Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX: Ascorbate protects endothelial barrier function during septic insult: Role of protein phosphatase type 2A. Free Radic Biol Med 2010;48:128-135.
  185. Roy J, Galano JM, Durand T, Le Guennec JY, Lee JC: Physiological role of reactive oxygen species as promoters of natural defenses. FASEB J 2017;31:3729-3745.
  186. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, Dong W: ROS and ROS-Mediated Cellular Signaling. Oxid Med Cell Longev 2016;2016:4350965.
  187. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK: Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ Res 2018;122:877-902.
  188. Corcoran SE, O'Neill LA: HIF1alpha and metabolic reprogramming in inflammation. J Clin Invest 2016;126:3699-3707.
  189. Bonello S, Zahringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, Gorlach A: Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol 2007;27:755-761.
  190. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB: Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem 2003;278:24233-24241.
  191. Schoonbroodt S, Ferreira V, Best-Belpomme M, Boelaert JR, Legrand-Poels S, Korner M, Piette J: Crucial role of the amino-terminal tyrosine residue 42 and the carboxyl-terminal PEST domain of I kappa B alpha in NF- kappa B activation by an oxidative stress. J Immunol 2000;164:4292-4300.
  192. Wu X, Xu F, Liu J, Wang G: Comparative study of dendritic cells matured by using IL-1beta, IL-6, TNF-alpha and prostaglandins E2 for different time span. Exp Ther Med 2017;14:1389-1394.
  193. Vega-Ramos J, Roquilly A, Zhan Y, Young LJ, Mintern JD, Villadangos JA: Inflammation conditions mature dendritic cells to retain the capacity to present new antigens but with altered cytokine secretion function. J Immunol 2014;193:3851-3859.
  194. Turner MD, Nedjai B, Hurst T, Pennington DJ: Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014;1843:2563-2582.
  195. Fullerton JN, Gilroy DW: Resolution of inflammation: a new therapeutic frontier. Nature reviews Drug discovery 2016;15:551-567.
  196. Shu X, Keller TCt, Begandt D, Butcher JT, Biwer L, Keller AS, Columbus L, Isakson BE: Endothelial nitric oxide synthase in the microcirculation. Cell Mol Life Sci 2015;72:4561-4575.
  197. Serhan CN, Chiang N, Dalli J, Levy BD: Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol 2014;7:a016311.
  198. Spite M, Serhan CN: Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res 2010;107:1170-1184.
  199. Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H: Negative Regulation of Cytokine Signaling in Immunity. Cold Spring Harb Perspect Biol 2018;10:a028571.
  200. Sun SC: A20 restricts inflammation via ubiquitin binding. Nat Immunol 2020;21:362-364.
  201. Proto JD, Doran AC, Gusarova G, Yurdagul A, Jr., Sozen E, Subramanian M, Islam MN, Rymond CC, Du J, Hook J, Kuriakose G, Bhattacharya J, Tabas I: Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity 2018;49:666-677 e666.
  202. Croasdell Lucchini A, Gachanja NN, Rossi AG, Dorward DA, Lucas CD: Epithelial Cells and Inflammation in Pulmonary Wound Repair Cells 2021;10:339.
  203. Raghavan S, Leo MD: Histamine Potentiates SARS-CoV-2 Spike Protein Entry Into Endothelial Cells. Front Pharmacol 2022;13:872736.
  204. Veenith T, Martin H, Le Breuilly M, Whitehouse T, Gao-Smith F, Duggal N, Lord JM, Mian R, Sarphie D, Moss P: High generation of reactive oxygen species from neutrophils in patients with severe COVID-19. Sci Rep 2022;12:10484.
  205. Tian M, Liu W, Li X, Zhao P, Shereen MA, Zhu C, Huang S, Liu S, Yu X, Yue M, Pan P, Wang W, Li Y, Chen X, Wu K, Luo Z, Zhang Q, Wu J: HIF-1alpha promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19. Signal Transduct Target Ther 2021;6:308.
  206. Morris DR, Qu Y, Agrawal A, Garofalo RP, Casola A: HIF-1alpha Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus. Viruses 2020;12:1088.
  207. Ling L, Chen Z, Lui G, Wong CK, Wong WT, Ng RWY, Tso EYK, Fung KSC, Chan V, Yeung ACM, Hui DSC, Chan PKS: Longitudinal Cytokine Profile in Patients With Mild to Critical COVID-19. Front Immunol 2021;12:763292.
  208. Gu Y, Zuo X, Zhang S, Ouyang Z, Jiang S, Wang F, Wang G: The Mechanism behind Influenza Virus Cytokine Storm. Viruses 2021;13:1362.
  209. Lage SL, Amaral EP, Hilligan KL, Laidlaw E, Rupert A, Namasivayan S, Rocco J, Galindo F, Kellogg A, Kumar P, Poon R, Wortmann GW, Shannon JP, Hickman HD, Lisco A, Manion M, Sher A, Sereti I: Persistent Oxidative Stress and Inflammasome Activation in CD14(high)CD16(-) Monocytes From COVID-19 Patients. Front Immunol 2021;12:799558.
  210. Lim JY, Oh E, Kim Y, Jung WW, Kim HS, Lee J, Sul D: Enhanced oxidative damage to DNA, lipids, and proteins and levels of some antioxidant enzymes, cytokines, and heat shock proteins in patients infected with influenza H1N1 virus. Acta Virol 2014;58:253-260.
  211. Nin N, Sanchez-Rodriguez C, Ver LS, Cardinal P, Ferruelo A, Soto L, Deicas A, Campos N, Rocha O, Ceraso DH, El-Assar M, Ortin J, Fernandez-Segoviano P, Esteban A, Lorente JA: Lung histopathological findings in fatal pandemic influenza A (H1N1). Med Intensiva 2012;36:24-31.
  212. Lee JS, Park S, Jeong HW, Ahn JY, Choi SJ, Lee H, Choi B, Nam SK, Sa M, Kwon JS, Jeong SJ, Lee HK, Park SH, Park SH, Choi JY, Kim SH, Jung I, Shin EC: Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci Immunol 2020;5:eabd1554.
  213. Kim H, Jang M, Kim Y, Choi J, Jeon J, Kim J, Hwang YI, Kang JS, Lee WJ: Red ginseng and Vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus/H1N1 infection. J Pharm Pharmacol 2016;68:406-420.
  214. Fisher BJ, Seropian IM, Kraskauskas D, Thakkar JN, Voelkel NF, Fowler AA, 3rd, Natarajan R: Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med 2011;39:1454-1460.
  215. Huang A, Vita JA, Venema RC, Keaney JF, Jr.: Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 2000;275:17399-17406.
  216. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER: L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 2001;276:40-47.
  217. Varadharaj S, Steinhour E, Hunter MG, Watkins T, Baran CP, Magalang U, Kuppusamy P, Zweier JL, Marsh CB, Natarajan V, Parinandi NL: Vitamin C-induced activation of phospholipase D in lung microvascular endothelial cells: regulation by MAP kinases. Cell Signal 2006;18:1396-1407.
  218. Granger M, Eck P: Dietary Vitamin C in Human Health. Adv Food Nutr Res 2018;83:281-310.
  219. Carcamo JM, Pedraza A, Borquez-Ojeda O, Zhang B, Sanchez R, Golde DW: Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IkappaBalpha kinase beta. Mol Cell Biol 2004;24:6645-6652.
  220. Osipyants AI, Poloznikov AA, Smirnova NA, Hushpulian DM, Khristichenko AY, Chubar TA, Zakhariants AA, Ahuja M, Gaisina IN, Thomas B, Brown AM, Gazaryan IG, Tishkov VI: L-ascorbic acid: A true substrate for HIF prolyl hydroxylase? Biochimie 2018;147:46-54.
  221. Trinh TA, Hoang TX, Kim JY: All-trans retinoic acid increases NF-kappaB activity in PMA-stimulated THP- 1 cells upon unmethylated CpG challenge by enhancing cell surface TLR9 expression. Mol Cell Biochem 2020;473:167-177.
  222. Alatshan A, Kovacs GE, Aladdin A, Czimmerer Z, Tar K, Benko S: All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage. Cells 2020;9:1591.
  223. Wang X, Allen C, Ballow M: Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol 2007;27:193-200.
  224. Austenaa LM, Carlsen H, Hollung K, Blomhoff HK, Blomhoff R: Retinoic acid dampens LPS-induced NF- kappaB activity: results from human monoblasts and in vivo imaging of NF-kappaB reporter mice. J Nutr Biochem 2009;20:726-734.
  225. Nurrahmah QI, Madhyastha R, Madhyastha H, Purbasari B, Maruyama M, Nakajima Y: Retinoic acid abrogates LPS-induced inflammatory response via negative regulation of NF-kappa B/miR-21 signaling. Immunopharmacol Immunotoxicol 2021;43:299-308.
  226. Moreno-Vinasco L, Verbout NG, Fryer AD, Jacoby DB: Retinoic acid prevents virus-induced airway hyperreactivity and M2 receptor dysfunction via anti-inflammatory and antiviral effects. Am J Physiol Lung Cell Mol Physiol 2009;297:L340-346.
  227. Janjetovic Z, Zmijewski MA, Tuckey RC, DeLeon DA, Nguyen MN, Pfeffer LM, Slominski AT: 20-Hydroxycholecalciferol, product of Vitamin D3 hydroxylation by P450scc, decreases NF-kappaB activity by increasing IkappaB alpha levels in human keratinocytes. PLoS One 2009;4:e5988.
  228. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, Goleva E: Vitamin D inhibits monocyte/ macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012;188:2127-2135.
  229. Dauletbaev N, Herscovitch K, Das M, Chen H, Bernier J, Matouk E, Berube J, Rousseau S, Lands LC: Down- regulation of IL-8 by high-dose Vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1. Br J Pharmacol 2015;172:4757-4771.
  230. Wang Q, He Y, Shen Y, Zhang Q, Chen D, Zuo C, Qin J, Wang H, Wang J, Yu Y: Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4. J Biol Chem 2014;289:11681-11694.
  231. Liang S, Cai J, Li Y, Yang R: 1, 25DihydroxyVitamin D3 induces macrophage polarization to M2 by upregulating Tcell Igmucin3 expression. Mol Med Rep 2019;19:3707-3713.
  232. Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC: Vitamin D receptor inhibits nuclear factor kappaB activation by interacting with IkappaB kinase beta protein. J Biol Chem 2013;288:19450-19458.
  233. Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC: Increased NF-kappaB activity in fibroblasts lacking the Vitamin D receptor. Am J Physiol Endocrinol Metab 2006;291:E315-322.
  234. Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, Sheikh A, Griffiths CJ: Vitamin D for the management of asthma. Cochrane Database Syst Rev 2016;9:CD011511.
  235. Li X, He J, Yu M, Sun J: The efficacy of Vitamin D therapy for patients with COPD: a meta-analysis of randomized controlled trials. Ann Palliat Med 2020;9:286-297.
  236. Barrea L, Grant WB, Frias-Toral E, Vetrani C, Verde L, de Alteriis G, Docimo A, Savastano S, Colao A, Muscogiuri G: Dietary Recommendations for Post-COVID-19 Syndrome. Nutrients 2022;14:1305.
  237. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Griffiths CJ, Janssens W, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, et al.: Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583.
  238. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP: Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020;12:988.
  239. Rocksen D, Ekstrand-Hammarstrom B, Johansson L, Bucht A: Vitamin E reduces transendothelial migration of neutrophils and prevents lung injury in endotoxin-induced airway inflammation. Am J Respir Cell Mol Biol 2003;28:199-207.
  240. Wang Y, Jiang Q: gamma-Tocotrienol inhibits lipopolysaccharide-induced interlukin-6 and granulocyte colony-stimulating factor by suppressing C/EBPbeta and NF-kappaB in macrophages. J Nutr Biochem 2013;24:1146-1152.
  241. Wang Y, Park NY, Jang Y, Ma A, Jiang Q: Vitamin E gamma-Tocotrienol Inhibits Cytokine-Stimulated NF- kappaB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids. J Immunol 2015;195:126-133.
  242. Yang C, Jiang Q: Vitamin E delta-tocotrienol inhibits TNF-alpha-stimulated NF-kappaB activation by up- regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. J Nutr Biochem 2019;64:101-109.
  243. Das T, Chen Z, Hendriks RW, Kool M: A20/Tumor Necrosis Factor alpha-induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models. Front Immunol 2018;9:104.
  244. Kim MH, Jeong HJ: Zinc Oxide Nanoparticles Suppress LPS-Induced NF-kappaB Activation by Inducing A20, a Negative Regulator of NF-kappaB, in RAW 264.7 Macrophages. J Nanosci Nanotechnol 2015;15:6509- 6515.
  245. von Bulow V, Rink L, Haase H: Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-alpha and IL-1 beta production in monocytes by elevation of guanosine 3',5'-cyclic monophosphate. J Immunol 2005;175:4697-4705.
  246. von Bulow V, Dubben S, Engelhardt G, Hebel S, Plumakers B, Heine H, Rink L, Haase H: Zinc-dependent suppression of TNF-alpha production is mediated by protein kinase A-induced inhibition of Raf-1, I kappa B kinase beta, and NF-kappa B. J Immunol 2007;179:4180-4186.
  247. Takahashi N, Tetsuka T, Uranishi H, Okamoto T: Inhibition of the NF-kappaB transcriptional activity by protein kinase A. Eur J Biochem 2002;269:4559-4565.
  248. Constantino L, Goncalves RC, Giombelli VR, Tomasi CD, Vuolo F, Kist LW, de Oliveira GM, Pasquali MA, Bogo MR, Mauad T, Horn A, Jr., Melo KV, Fernandes C, Moreira JC, Ritter C, Dal-Pizzol F: Regulation of lung oxidative damage by endogenous superoxide dismutase in sepsis. Intensive Care Med Exp 2014;2:17.
  249. Malpuech-Brugere C, Nowacki W, Rock E, Gueux E, Mazur A, Rayssiguier Y: Enhanced tumor necrosis factoralpha production following endotoxin challenge in rats is an early event during Magnesium deficiency. Biochim Biophys Acta 1999;1453:35-40.
  250. Zhang L, Yang L, Xie X, Zheng H, Zheng H, Zhang L, Liu C, Piao JG, Li F: Baicalin Magnesium Salt Attenuates Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting of TLR4/NF-kappaB Signaling Pathway. J Immunol Res 2021;2021:6629531.
  251. Libako P, Nowacki W, Castiglioni S, Mazur A, Maier JA: Extracellular Magnesium and calcium blockers modulate macrophage activity. Magnes Res 2016;29:11-21.
  252. Bussiere FI, Gueux E, Rock E, Mazur A, Rayssiguier Y: Protective effect of calcium deficiency on the inflammatory response in Magnesium-deficient rats. Eur J Nutr 2002;41:197-202.
  253. Reina-Campos M, Scharping NE, Goldrath AW: CD8(+) T cell metabolism in infection and cancer. Nat Rev Immunol 2021;21:718-738.
  254. Bhat P, Leggatt G, Waterhouse N, Frazer IH: Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis 2017;8:e2836.
  255. McMaster SR, Wilson JJ, Wang H, Kohlmeier JE: Airway-Resident Memory CD8 T Cells Provide Antigen- Specific Protection against Respiratory Virus Challenge through Rapid IFN-gamma Production. J Immunol 2015;195:203-209.
  256. Schmidt ME, Varga SM: The CD8 T Cell Response to Respiratory Virus Infections. Front Immunol 2018;9:678.
  257. McNally A, Hill GR, Sparwasser T, Thomas R, Steptoe RJ: CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci U S A 2011;108:7529-7534.
  258. Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM: Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 2015;16:871-879.
  259. de Goer de Herve MG, Jaafoura S, Vallee M, Taoufik Y: FoxP3(+) regulatory CD4 T cells control the generation of functional CD8 memory. Nat Commun 2012;3:986.
  260. Erickson JJ, Lu P, Wen S, Hastings AK, Gilchuk P, Joyce S, Shyr Y, Williams JV: Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype. J Immunol 2015;195:4319-4330.
  261. Rutigliano JA, Sharma S, Morris MY, Oguin TH, 3rd, McClaren JL, Doherty PC, Thomas PG: Highly pathological influenza A virus infection is associated with augmented expression of PD-1 by functionally compromised virus-specific CD8+ T cells. J Virol 2014;88:1636-1651.
  262. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, Feng Z, Zhang Y, Wu Y, Chen Y: Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol 2020;11:827.
  263. Dzhagalov I, Chambon P, He YW: Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J Immunol 2007;178:2113-2121.
  264. Guo Y, Lee YC, Brown C, Zhang W, Usherwood E, Noelle RJ: Dissecting the role of retinoic acid receptor isoforms in the CD8 response to infection. J Immunol 2014;192:3336-3344.
  265. Jansa P, Forejt J: A novel type of retinoic acid response element in the second intron of the mouse H2Kb gene is activated by the RAR/RXR heterodimer. Nucleic Acids Res 1996;24:694-701.
  266. Tan X, Sande JL, Pufnock JS, Blattman JN, Greenberg PD: Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. J Virol 2011;85:8316-8327.
  267. Yuzefpolskiy Y, Baumann FM, Penny LA, Studzinski GP, Kalia V, Sarkar S: Vitamin D receptor signals regulate effector and memory CD8 T cell responses to infections in mice. J Nutr 2014;144:2073-2082.
  268. Li P, Zhu X, Cao G, Wu R, Li K, Yuan W, Chen B, Sun G, Xia X, Zhang H, Wang X, Yin Z, Lu L, Gao Y: 1alpha,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells. J Immunother Cancer 2022;10:e003477.
  269. Zhu Y, van Essen D, Saccani S: Cell-type-specific control of enhancer activity by H3K9 trimethylation. Mol Cell 2012;46:408-423.
  270. Kroening PR, Barnes TW, Pease L, Limper A, Kita H, Vassallo R: Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. J Immunol 2008;181:1536-1547.
  271. Jeong YJ, Hong SW, Kim JH, Jin DH, Kang JS, Lee WJ, Hwang YI: Vitamin C-treated murine bone marrow- derived dendritic cells preferentially drive naive T cells into Th1 cells by increased IL-12 secretions. Cell Immunol 2011;266:192-199.
  272. Jeong YJ, Kim JH, Hong JM, Kang JS, Kim HR, Lee WJ, Hwang YI: Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8(+) memory T cell production capacity of these cells in vivo. Immunobiology 2014;219:554-564.
  273. Luchtel RA, Bhagat T, Pradhan K, Jacobs WR, Jr., Levine M, Verma A, Shenoy N: High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc Natl Acad Sci U S A 2020;117:1666-1677.
  274. Pilipow K, Scamardella E, Puccio S, Gautam S, De Paoli F, Mazza EM, De Simone G, Polletti S, Buccilli M, Zanon V, Di Lucia P, Iannacone M, Gattinoni L, Lugli E: Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity. JCI Insight 2018;3:e122299.
  275. Kanellopoulou C, George AB, Masutani E, Cannons JL, Ravell JC, Yamamoto TN, Smelkinson MG, Jiang PD, Matsuda-Lennikov M, Reilley J, Handon R, Lee PH, Miller JR, Restifo NP, Zheng L, Schwartzberg PL, Young M, Lenardo MJ: Mg(2+) regulation of kinase signaling and immune function. J Exp Med 2019;216:1828-1842.
  276. Shipkova M, Wieland E: Surface markers of lymphocyte activation and markers of cell proliferation. Clin Chim Acta 2012;413:1338-1349.
  277. Lotscher J, Marti ILAA, Kirchhammer N, Cribioli E, Giordano Attianese GMP, Trefny MP, Lenz M, Rothschild SI, Strati P, Kunzli M, Lotter C, Schenk SH, Dehio P, Loliger J, Litzler L, Schreiner D, Koch V, Page N, Lee D, Grahlert J, et al.: Magnesium sensing via LFA-1 regulates CD8(+) T cell effector function. Cell 2022;185:585- 602 e529.
  278. Harker N, Naito T, Cortes M, Hostert A, Hirschberg S, Tolaini M, Roderick K, Georgopoulos K, Kioussis D: The CD8alpha gene locus is regulated by the Ikaros family of proteins. Mol Cell 2002;10:1403-1415.
  279. Bilic I, Koesters C, Unger B, Sekimata M, Hertweck A, Maschek R, Wilson CB, Ellmeier W: Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the Zinc finger protein MAZR. Nat Immunol 2006;7:392-400.
  280. Omilusik KD, Best JA, Yu B, Goossens S, Weidemann A, Nguyen JV, Seuntjens E, Stryjewska A, Zweier C, Roychoudhuri R, Gattinoni L, Bird LM, Higashi Y, Kondoh H, Huylebroeck D, Haigh J, Goldrath AW: Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection. J Exp Med 2015;212:2027-2039.
  281. Clambey ET, Collins B, Young MH, Eberlein J, David A, Kappler JW, Marrack P: The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells. PLoS One 2013;8:e57435.
  282. Luckheeram RV, Zhou R, Verma AD, Xia B: CD4(+)T cells: differentiation and functions. Clin Dev Immunol 2012;2012:925135.
  283. Olatunde AC, Hale JS, Lamb TJ: Cytokine-skewed Tfh cells: functional consequences for B cell help. Trends Immunol 2021;42:536-550.
  284. Zhu J, Yamane H, Paul WE: Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445-489.
  285. Gil-Etayo FJ, Garcinuno S, Utrero-Rico A, Cabrera-Marante O, Arroyo-Sanchez D, Mancebo E, Pleguezuelo DE, Rodriguez-Frias E, Allende LM, Morales-Perez P, Castro-Panete MJ, Lalueza A, Lumbreras C, Paz-Artal E, Serrano A: An Early Th1 Response Is a Key Factor for a Favorable COVID-19 Evolution. Biomedicines 2022;10:296.
  286. Brown DM, Lee S, Garcia-Hernandez Mde L, Swain SL: Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 2012;86:6792- 6803.
  287. Zhang S, Zhang H, Zhao J: The role of CD4 T cell help for CD8 CTL activation. Biochem Biophys Res Commun 2009;384:405-408.
  288. Huang S, He Q, Zhou L: T cell responses in respiratory viral infections and chronic obstructive pulmonary disease. Chin Med J (Engl) 2021;134:1522-1534.
  289. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, Treuting PM, Rudensky AY : A Distinct Function of Regulatory T Cells in Tissue Protection. Cell 2015;162:1078-1089.
  290. Muramatsu M, Yoshida R, Yokoyama A, Miyamoto H, Kajihara M, Maruyama J, Nao N, Manzoor R, Takada A: Comparison of antiviral activity between IgA and IgG specific to influenza virus hemagglutinin: increased potential of IgA for heterosubtypic immunity. PLoS One 2014;9:e85582.
  291. Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Claer L, Quentric P, Fadlallah J, Devilliers H, Ghillani P, Gunn C, Hockett R, Mudumba S, Guihot A, Luyt CE, Mayaux J, Beurton A, Fourati S, Bruel T, Schwartz O, et al.: IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med 2021;13:eabd2223.
  292. Walsh EE, Falsey AR: Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults. J Infect Dis 2004;190:373-378.
  293. van Erp EA, Luytjes W, Ferwerda G, van Kasteren PB: Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front Immunol 2019;10:548.
  294. Shen L, Li S, Zhu Y, Zhao J, Tang X, Li H, Xing H, Lu M, Frederick C, Huang C, Wong G, Wang C, Lan J: Clinical and laboratory-derived parameters of 119 hospitalized patients with coronavirus disease 2019 in Xiangyang, Hubei Province, China. J Infect 2020;81:147-178.
  295. Lalueza A, Folgueira D, Diaz-Pedroche C, Hernandez-Jimenez P, Ayuso B, Castillo C, Laureiro J, Trujillo H, Torres M, Lumbreras C: Severe lymphopenia in hospitalized patients with influenza virus infection as a marker of a poor outcome. Infect Dis (Lond) 2019;51:543-546.
  296. Gul A, Khan S, Arshad M, Anjum SI, Attaullah S, Ali I, Rauf A, Arshad A, Alghanem SM, Khan SN: Peripheral blood T cells response in human parainfluenza virus-associated lower respiratory tract infection in children. Saudi J Biol Sci 2020;27:2847-2852.
  297. Ramos-Fernandez JM, Moreno-Perez D, Antunez-Fernandez C, Milano-Manso G, Cordon-Martinez AM, Urda- Cardona A: [Lower lymphocyte response in severe cases of acute bronchiolitis due to respiratory syncytial virus]. An Pediatr (Engl Ed) 2018;88:315-321.
  298. Liu S, Huang Z, Fan R, Jia J, Deng X, Zou X, Li H, Cao B: Cycling and activated CD8(+) T lymphocytes and their association with disease severity in influenza patients. BMC Immunol 2022;23:40.
  299. Roman M, Calhoun WJ, Hinton KL, Avendano LF, Simon V, Escobar AM, Gaggero A, Diaz PV: Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response. Am J Respir Crit Care Med 1997;156:190-195.
  300. Pinto RA, Arredondo SM, Bono MR, Gaggero AA, Diaz PV: T helper 1/T helper 2 cytokine imbalance in respiratory syncytial virus infection is associated with increased endogenous plasma cortisol. Pediatrics 2006;117:e878-886.
  301. Guo-Parke H, Linden D, Mousnier A, Scott IC, Killick H, Borthwick LA, Fisher AJ, Weldon S, Taggart CC, Kidney JC: Altered Differentiation and Inflammation Profiles Contribute to Enhanced Innate Responses in Severe COPD Epithelium to Rhinovirus Infection. Front Med (Lausanne) 2022;9:741989.
  302. Liu Y, Qin T, Zhao X, Dong S, Zhu J, Peng D, Zhong J, Li T, Chen X: Skewed balance of regulatory T cell and inflammatory T cell in IL-17 defect with human metapneumovirus infection. Cell Immunol 2018;331:161- 167.
  303. Choreno-Parra JA, Jimenez-Alvarez LA, Cruz-Lagunas A, Rodriguez-Reyna TS, Ramirez-Martinez G, Sandoval-Vega M, Hernandez-Garcia DL, Choreno-Parra EM, Balderas-Martinez YI, Martinez-Sanchez ME, Marquez-Garcia E, Sciutto E, Moreno-Rodriguez J, Barreto-Rodriguez JO, Vazquez-Rojas H, Centeno- Saenz GI, Alvarado-Pena N, Salinas-Lara C, Sanchez-Garibay C, Galeana-Cadena D, et al.: Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1). Front Immunol 2021;12:593595.
  304. Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, DeVincenzo JP, de Haan CA, Wrammert J, Openshaw PJ, Chiu C, Mechanisms of Severe Acute Influenza Consortium I: Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus. Am J Respir Crit Care Med 2015;191:1040-1049.
  305. Oh JE, Song E, Moriyama M, Wong P, Zhang S, Jiang R, Strohmeier S, Kleinstein SH, Krammer F, Iwasaki A: Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Sci Immunol 2021;6:eabj5129.
  306. Kim MH, Kim HJ, Chang J: Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus. PLoS One 2019;14:e0220196.
  307. Chan RWY, Chan KCC, Lui GCY, Tsun JGS, Chan KYY, Yip JSK, Liu S, Yu MWL, Ng RWY, Chong KKL, Wang MH, Chan PKS, Li AM, Lam HS: Mucosal Antibody Response to SARS-CoV-2 in Paediatric and Adult Patients: A Longitudinal Study. Pathogens 2022;11:397.
  308. Smith-Norowitz TA, Mandal M, Joks R, Norowitz LT, Weaver D, Durkin HG, Bluth MH, Kohlhoff S: IgE anti- respiratory syncytial virus antibodies detected in serum of pediatric patients with asthma. Hum Immunol 2015;76:519-524.
  309. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007;204:1757-1764.
  310. Agrawal S, Ganguly S, Tran A, Sundaram P, Agrawal A: Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age. Aging (Albany NY) 2016;8:1223-1235.
  311. Zai K, Yuzuriha K, Kishimura A, Mori T, Katayama Y: Preparation of Complexes between Ovalbumin Nanoparticles and Retinoic Acid for Efficient Induction of Tolerogenic Dendritic Cells. Anal Sci 2018;34:1243-1248.
  312. Geissmann F, Revy P, Brousse N, Lepelletier Y, Folli C, Durandy A, Chambon P, Dy M: Retinoids regulate survival and antigen presentation by immature dendritic cells. J Exp Med 2003;198:623-634.
  313. Brown CC, Esterhazy D, Sarde A, London M, Pullabhatla V, Osma-Garcia I, Al-Bader R, Ortiz C, Elgueta R, Arno M, de Rinaldis E, Mucida D, Lord GM, Noelle RJ: Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 2015;42:499-511.
  314. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, Kuchroo VK: Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008;181:2277-2284.
  315. Stephensen CB, Rasooly R, Jiang X, Ceddia MA, Weaver CT, Chandraratna RA, Bucy RP: Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. J Immunol 2002;168:4495-4503.
  316. Iwata M, Eshima Y, Kagechika H: Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol 2003;15:1017-1025.
  317. Koning JJ, Rajaraman A, Reijmers RM, Konijn T, Pan J, Ware CF, Butcher EC, Mebius RE: Development of follicular dendritic cells in lymph nodes depends on retinoic acid-mediated signaling. Development 2021;148:dev199713.
  318. Suzuki K, Maruya M, Kawamoto S, Sitnik K, Kitamura H, Agace WW, Fagarasan S: The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut. Immunity 2010;33:71-83.
  319. Watanabe K, Sugai M, Nambu Y, Osato M, Hayashi T, Kawaguchi M, Komori T, Ito Y, Shimizu A: Requirement for Runx proteins in IgA class switching acting downstream of TGF-beta 1 and retinoic acid signaling. J Immunol 2010;184:2785-2792.
  320. Chen X, Welner RS, Kincade PW: A possible contribution of retinoids to regulation of fetal B lymphopoiesis. Eur J Immunol 2009;39:2515-2524.
  321. Chen X, Esplin BL, Garrett KP, Welner RS, Webb CF, Kincade PW: Retinoids accelerate B lineage lymphoid differentiation. J Immunol 2008;180:138-145.
  322. Chen Q, Ross AC: Vitamin A and immune function: retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells. Proc Natl Acad Sci U S A 2005;102:14142-14149.
  323. Ertesvag A, Aasheim HC, Naderi S, Blomhoff HK: Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK. Blood 2007;109:3865-3872.
  324. Lee BO, Rangel-Moreno J, Moyron-Quiroz JE, Hartson L, Makris M, Sprague F, Lund FE, Randall TD: CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J Immunol 2005;175:5827-5838.
  325. Marks E, Ortiz C, Pantazi E, Bailey CS, Lord GM, Waldschmidt TJ, Noelle RJ, Elgueta R: Retinoic Acid Signaling in B Cells Is Required for the Generation of an Effective T-Independent Immune Response. Front Immunol 2016;7:643.
  326. Ferreira GB, Gysemans CA, Demengeot J, da Cunha JP, Vanherwegen AS, Overbergh L, Van Belle TL, Pauwels F, Verstuyf A, Korf H, Mathieu C: 1, 25-DihydroxyVitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice. J Immunol 2014;192:4210-4220.
  327. Ferreira GB, van Etten E, Verstuyf A, Waer M, Overbergh L, Gysemans C, Mathieu C: 1, 25-DihydroxyVitamin D3 alters murine dendritic cell behaviour in vitro and in vivo. Diabetes Metab Res Rev 2011;27:933-941.
  328. Sheikh V, Kasapoglu P, Zamani A, Basiri Z, Tahamoli-Roudsari A, Alahgholi-Hajibehzad M: Vitamin D3 inhibits the proliferation of T helper cells, downregulate CD4(+) T cell cytokines and upregulate inhibitory markers. Hum Immunol 2018;79:439-445.
  329. Sloka S, Silva C, Wang J, Yong VW: Predominance of Th2 polarization by Vitamin D through a STAT6- dependent mechanism. J Neuroinflammation 2011;8:56.
  330. Zhou Q, Qin S, Zhang J, Zhon L, Pen Z, Xing T: 1, 25(OH)2D3 induces regulatory T cell differentiation by influencing the VDR/PLC-gamma1/TGF-beta1/pathway. Mol Immunol 2017;91:156-164.
  331. Wang Z, Wang Y, Xu B, Liu J, Ren Y, Dai Z, Cui D, Su X, Si S, Song SJ: Vitamin D improves immune function in immunosuppressant mice induced by glucocorticoid. Biomed Rep 2017;6:120-124.
  332. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE: Modulatory effects of 1, 25-dihydroxyVitamin D3 on human B cell differentiation. J Immunol 2007;179:1634-1647.
  333. Danner OK, Matthews LR, Francis S, Rao VN, Harvey CP, Tobin RP, Wilson KL, Alema-Mensah E, Newell Rogers MK, Childs EW: Vitamin D3 Suppresses Class II Invariant Chain Peptide Expression on Activated B-Lymphocytes: A Plausible Mechanism for Downregulation of Acute Inflammatory Conditions. J Nutr Metab 2016;2016:4280876.
  334. Treptow S, Grun J, Scholz J, Radbruch A, Heine G, Worm M: 9-cis Retinoic acid and 1.25-dihydroxyVitamin D3 drive differentiation into IgA(+) secreting plasmablasts in human naive B cells. Eur J Immunol 2021;51:125-137.
  335. Kim HW, Cho SI, Bae S, Kim H, Kim Y, Hwang YI, Kang JS, Lee WJ: Vitamin C Up-regulates Expression of CD80, CD86 and MHC Class II on Dendritic Cell Line, DC-1 Via the Activation of p38 MAPK. Immune Netw 2012;12:277-283.
  336. Sasidharan Nair V, Song MH, Oh KI: Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet- Dependent Manner. J Immunol 2016;196:2119-2131.
  337. Liu Z, Cao W, Xu L, Chen X, Zhan Y, Yang Q, Liu S, Chen P, Jiang Y, Sun X, Tao Y, Hu Y, Li C, Wang Q, Wang Y, Chen CD, Shi Y, Zhang X: The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. J Mol Cell Biol 2015;7:505-516.
  338. Song MH, Nair VS, Oh KI: Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB Rep 2017;50:49-54.
  339. Ichiyama K, Mitsuzumi H, Zhong M, Tai A, Tsuchioka A, Kawai S, Yamamoto I, Gohda E: Promotion of IL-4- and IL-5-dependent differentiation of anti-mu-primed B cells by ascorbic acid 2-glucoside. Immunol Lett 2009;122:219-226.
  340. Qi T, Sun M, Zhang C, Chen P, Xiao C, Chang X: Ascorbic Acid Promotes Plasma Cell Differentiation through Enhancing TET2/3-Mediated DNA Demethylation. Cell Rep 2020;33:108452.
  341. Woo A, Kim JH, Jeong YJ, Maeng HG, Lee YT, Kang JS, Lee WJ, Hwang YI: Vitamin C acts indirectly to modulate isotype switching in mouse B cells. Anat Cell Biol 2010;43:25-35.
  342. Quek AML, Ooi DSQ, Teng O, Chan CY, Ng GJL, Ng MY, Yee S, Cheong EW, Weng R, Cook AR, Hartman M, Angeli V, Tambyah PA, Seet RCS: Zinc and Vitamin C intake increases spike and neutralising antibody production following SARS-CoV-2 infection. Clin Transl Med 2022;12:e731.
  343. George MM, Subramanian Vignesh K, Landero Figueroa JA, Caruso JA, Deepe GS, Jr.: Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance. J Immunol 2016;197:1864-1876.
  344. Song XT, Evel-Kabler K, Shen L, Rollins L, Huang XF, Chen SY: A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat Med 2008;14:258-265.
  345. Maywald M, Wang F, Rink L: The Intracellular Free Zinc Level Is Vital for Treg Function and a Feasible Tool to Discriminate between Treg and Activated Th Cells. Int J Mol Sci 2018;19:3575.
  346. Powell MD, Read KA, Sreekumar BK, Oestreich KJ: Ikaros Zinc Finger Transcription Factors: Regulators of Cytokine Signaling Pathways and CD4(+) T Helper Cell Differentiation. Front Immunol 2019;10:1299.
  347. Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, Engelhardt KR, Xu X, Chen R, Alvarez L, Berlinguer-Palmini R, Bull KR, Cawthorne E, Cribbs AP, Crockford TL, Dang TS, Fearn A, Fenech EJ, de Jong SJ, Lagerholm BC, et al.: An essential role for the Zn(2+) transporter ZIP7 in B cell development. Nat Immunol 2019;20:350-361.
  348. Miyai T, Hojyo S, Ikawa T, Kawamura M, Irie T, Ogura H, Hijikata A, Bin BH, Yasuda T, Kitamura H, Nakayama M, Ohara O, Yoshida H, Koseki H, Mishima K, Fukada T: Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. Proc Natl Acad Sci U S A 2014;111:11780-11785.
  349. Fields S, Ternyak K, Gao H, Ostraat R, Akerlund J, Hagman J: The 'Zinc knuckle' motif of Early B cell Factor is required for transcriptional activation of B cell-specific genes. Mol Immunol 2008;45:3786-3796.
  350. Jurado S, Gleeson K, O'Donnell K, Izon DJ, Walkley CR, Strasser A, Tarlinton DM, Heierhorst J: The Zinc- finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. J Exp Med 2012;209:1629-1639.
  351. Arenzana TL, Smith-Raska MR, Reizis B: Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes. Blood 2009;113:5857-5867.
  352. Kosan C, Saba I, Godmann M, Herold S, Herkert B, Eilers M, Moroy T: Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation. Immunity 2010;33:917-928.
  353. Mega T, Lupia M, Amodio N, Horton SJ, Mesuraca M, Pelaggi D, Agosti V, Grieco M, Chiarella E, Spina R, Moore MA, Schuringa JJ, Bond HM, Morrone G: Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B-lymphoid differentiation of primary hematopoietic progenitors. Cell Cycle 2011;10:2129- 2139.
  354. Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M: Essential role of the Zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells. PLoS One 2013;8:e58022.
  355. Hojyo S, Miyai T, Fujishiro H, Kawamura M, Yasuda T, Hijikata A, Bin BH, Irie T, Tanaka J, Atsumi T, Murakami M, Nakayama M, Ohara O, Himeno S, Yoshida H, Koseki H, Ikawa T, Mishima K, Fukada T: Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. Proc Natl Acad Sci U S A 2014;111:11786-11791.
  356. Tepaamorndech S, Oort P, Kirschke CP, Cai Y, Huang L: ZNT7 binds to CD40 and influences CD154-triggered p38 MAPK activity in B lymphocytes-a possible regulatory mechanism for Zinc in immune function. FEBS Open Bio 2017;7:675-690.
  357. Klein U, Tu Y, Stolovitzky GA, Keller JL, Haddad J, Jr., Miljkovic V, Cattoretti G, Califano A, Dalla-Favera R: Transcriptional analysis of the B cell germinal center reaction. Proc Natl Acad Sci U S A 2003;100:2639- 2644.
  358. Rolles B, Maywald M, Rink L: Intracellular Zinc during cell activation and Zinc deficiency. J Trace Elem Med Biol 2021;68:126864.
  359. Sakurai N, Maeda M, Lee SU, Ishikawa Y, Li M, Williams JC, Wang L, Su L, Suzuki M, Saito TI, Chiba S, Casola S, Yagita H, Teruya-Feldstein J, Tsuzuki S, Bhatia R, Maeda T: The LRF transcription factor regulates mature B cell development and the germinal center response in mice. J Clin Invest 2011;121:2583-2598.
  360. Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, Erikci E, Smyth GK, Chowdhury K, Tarlinton D, Corcoran LM: The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. J Exp Med 2014;211:827-840.
  361. Tellier J, Shi W, Minnich M, Liao Y, Crawford S, Smyth GK, Kallies A, Busslinger M, Nutt SL: Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol 2016;17:323-330.
  362. Xie B, Khoyratty TE, Abu-Shah E, P FC, MacLean AJ, Pirgova G, Hu Z, Ahmed AA, Dustin ML, Udalova IA, Arnon TI: The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation. J Immunol 2021;206:1515-1527.
  363. Qu B, Al-Ansary D, Kummerow C, Hoth M, Schwarz EC: ORAI-mediated calcium influx in T cell proliferation, apoptosis and tolerance. Cell Calcium 2011;50:261-269.
  364. Krishnamoorthy M, Buhari FHM, Zhao T, Brauer PM, Burrows K, Cao EY, Moxley-Paquette V, Mortha A, Zuniga-Pflucker JC, Treanor B: The ion channel TRPM7 is required for B cell lymphopoiesis. Sci Signal 2018;11:eaan2693.
  365. Gotru SK, Gil-Pulido J, Beyersdorf N, Diefenbach A, Becker IC, Vogtle T, Remer K, Chubanov V, Gudermann T, Hermanns HM, Nieswandt B, Kerkau T, Zernecke A, Braun A: Cutting Edge: Imbalanced Cation Homeostasis in MAGT1-Deficient B Cells Dysregulates B Cell Development and Signaling in Mice. J Immunol 2018;200:2529-2534.
  366. Mwanza-Lisulo M, Kelly P: Potential for use of retinoic acid as an oral vaccine adjuvant. Philos Trans R Soc Lond B Biol Sci 2015;370:20140145.
  367. Dhawan M, Priyanka, Choudhary OP: Immunomodulatory and therapeutic implications of Vitamin D in the management of COVID-19. Hum Vaccin Immunother 2022;18:2025734.s

VitaminDWiki - Immunity category contains

262 items in Immunity category

    see also

Virus category listing has 1336 items along with related searches

Overview Influenza and vitamin D
Vitamin D helps both the innate and adaptive immune systems fight COVID-19 – Jan 2022
Vitamin D aids the clearing out of old cells (autophagy) – many studies
600,000 IU of Vitamin D (total) allowed previously weak immune systems to fight off a virus antigen - Nov 2020
Search for treg OR "t-cell" in VitaminDWiki 1440 items as of Jan 2020
141 VitaminDWiki pages contained "infection" in title (June 2021)
Search VitaminDWik for BACTERIA in title 25 items as of Aug 2019
Vitamin D and the Immune System – chapter Aug 2019
7X less risk of influenza if Vitamin D levels higher than 30 ng – Oct 2017
Common cold prevented and treated by Vitamin D, Vitamin C, Zinc, and Echinacea – review April 2018
Vitamin D improves T Cell immunity – RCT Feb 2016
Immune system - great 11-minute animated video - Aug 2021
   Only the brain is more complex, nothing about Vitamin D

18 titles in VitaminDWiki contained INNATE or ADAPTIVE as of Jan 2023
Increasing publications on vitamin D and Infection
Image

47 studies are in both Immunity and Virus categories

VitaminDWiki - 47 studies in both categories Immunity and Virus

This list is automatically updated


Created by admin. Last Modification: Tuesday December 6, 2022 16:16:47 GMT-0000 by admin. (Version 7)

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