TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target
Front. Pharmacol., 15 January 2021 | https://doi.org/10.3389/fphar.2020.601685
Gillina F. G. Bezemer1,2* and Johan Garssen1,3
1 Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
2 Impact Station, Hilversum, Netherlands
3 Department of Immunology, Nutricia Research BV, Utrecht, Netherlands
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By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.
Vitamin D (clipped from PDF)_
During the first wave of Covid-19, low Vitamin D levels have been found in the vulnerable aging population in Spain, Italy and Switzerland which pointed towards the potential of vitamin D in prevention of COVID-19 infection and mortality (Ilie et al., 2020). Vitamin D deficiency has indeed been found to contribute to ARDS and a narrative review on vitamin D shows accumulation of evidence that vitamin D supplementation could reduce risk of COVID-19 infections and deaths (Grant et al., 2020). Vitamin D is known to promote innate immune response against viral infection and a role for TLRs has been proposed in explaining the underlying mechanism. Martinez-Moreno et al showed that innate immune response against the dengue virus (DENV) infection, a public health problem worldwide, can be improved by vitamin D supplementation.
Their study showed that an oral supplement of 4000 IU/day of vitamin D3 significantly decreased TLR9 protein levels and the mRNA abundance ofTLR3, TLR7, and TLR9 in human. The lower dose of, 1000 IU/day of vitamin D only decreased the TLR9 protein level in human monocte-derived DCs infected with DENV. The finding is especially interesting because TLR9 activation, through mtDNA, contributes to DENV-induced immune activation (Martinez Moreno et al., 2020). A study performed in 2010 also showed that intracellular TLRs are differentially regulated by vitamin D3, with TLR9 being down-regulated by vitamin D3 exposure whereas TLR3 was unaffected (Dickie et al., 2010). The study by Dickie et al showed that vitamin D3 decreased TLR9 expression in monocytes and had a downstream functional effect as these cells subsequently secreted less IL-6 in response to TLR9 challenge.