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Long-COVID can hide in the body for years in scores of locations – Sept 2023

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)

Nature Immunology Sept 2023 https://doi.org/10.1038/s41590-023-01601-2
Amy D. Proal, Michael B. VanElzakker, Soo Aleman, Katie Bach, Brittany P. Boribong, Marcus Buggert, Sara Cherry, Daniel S. Chertow, Helen E. Davies, Christopher L. Dupont, Steven G. Deeks, William Eimer, E. Wesley Ely, Alessio Fasano, Marcelo Freire, Linda N. Geng, Diane E. Griffin, Timothy J. Henrich, Akiko Iwasaki, David Izquierdo-Garcia, Michela Locci, Saurabh Mehandru, Mark M. Painter, Michael J. Peluso, …E. John Wherry

Table of Contents


Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—persist in tissue as a ‘reservoir’. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

Locations in the body


Research suggesions

Major areas of opportunity for research into a SARS-CoV-2 reservoir in PASC

  • Which PASC cell and tissue types harbor SARS-CoV-2 RNA or protein?
    • Is there a preference for persistence in certain cell or tissue types?
  • Is SARS-CoV-2 RNA identified in PASC samples transcriptionally active, translating, replicating or infectious?
  • Is the presence of a SARS-CoV-2 reservoir sufficient to drive PASC symptoms?
    • Are SARS-CoV-2 RNA and proteins also identified in samples collected from post-COVID-19 individuals without PASC?
    • If yes, what factors differentiate SARS-CoV-2 persistence in PASC from persistence in asymptomatic individuals?
  • Do particular classes of symptoms tend to be driven by the location of the reservoir—for example, dyspnea from a lung reservoir or gastrointestinal symptoms from a gut reservoir?
  • Do measurements of SARS-CoV-2 protein or antibody responses in body fluids correlate with SARS-COV-2 persistence in tissue?
  • Can the transcriptional program of circulating immune cells be used as a biosensor of SARS-CoV-2 persistence in tissue?
  • Does T cell exhaustion correlate with SARS-CoV-2 persistence in PASC?
  • Are neutralizing antibody responses qualitatively different in patients with PASC?
  • By what mechanisms can SARS-CoV-2 evade immune detection?
    • Do such mechanisms differ by cell or tissue type, or by viral variant?
    • Do viral mutations and selection contribute to persistence?
  • Can the spike protein travel via EVs into the bloodstream?
  • Does a SARS-CoV-2 reservoir or protein contribute to fibrin/ amyloid microclotting, platelet activation or related vasculature issues in PASC?
  • Does a SARS-CoV-2 reservoir in PASC correlate with the reactivation of other pathogens such as herpesviruses?
  • Does a SARS-CoV-2 reservoir in PASC correlate with changes in human endogenous retrovirus activity?
  • Can a SARS-CoV-2 reservoir alter the local transcriptome or epigenome?
  • Does a SARS-CoV-2 reservoir in PASC correlate with the disruption of microbiome composition or activity?
    • If so, is disruption a cause or consequence of PASC?
  • Is a SARS-CoV-2 reservoir associated with host epithelial barrier breakdown in PASC?
    • Does this facilitate the translocation viral protein or bacterial/fungal organisms into blood?
  • Can SARS-CoV-2 persistence or the reactivation of other latent pathogens lead to cross-reactive antibody responses in PASC blood or tissue?

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Attached files

ID Name Comment Uploaded Size Downloads
20080 Reservoir locations.jpg admin 09 Sep, 2023 204.78 Kb 117
20079 Reservoir ToC.jpg admin 09 Sep, 2023 53.83 Kb 110
20078 SARS-CoV-2 reservoir_CompressPdf.pdf admin 09 Sep, 2023 312.98 Kb 91