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

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; Etheresia Pretorius; David A Price; David Putrino; Richard H Scheuermann; Gene S Tan; Rudolph E Tanzi; Henry F VanBrocklin; Lael M Yonker; E John Wherry

doi:10.1038/s41590-023-01601-2

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

Nat Immunol. 2023 Oct;24(10):1616-1627. doi: 10.1038/s41590-023-01601-2. Epub 2023 Sep 4.

Authors

Amy D Proal¹, Michael B VanElzakker^{2

3}, Soo Aleman⁴, Katie Bach^{2

5}, Brittany P Boribong^{6

7

8}, Marcus Buggert⁹, Sara Cherry¹⁰, Daniel S Chertow^{11

12}, Helen E Davies¹³, Christopher L Dupont¹⁴, Steven G Deeks¹⁵, William Eimer^{8

16

17

18}, E Wesley Ely¹⁹, Alessio Fasano^{6

7

8}, Marcelo Freire²⁰, Linda N Geng²¹, Diane E Griffin²², Timothy J Henrich²³, Akiko Iwasaki^{24

25

26}, David Izquierdo-Garcia^{27

28}, Michela Locci²⁹, Saurabh Mehandru^{30

31}, Mark M Painter³², Michael J Peluso¹⁵, Etheresia Pretorius^{33

34}, David A Price^{35

36}, David Putrino³⁷, Richard H Scheuermann^{38

39

40}, Gene S Tan^{14

41}, Rudolph E Tanzi^{8

16

17

18}, Henry F VanBrocklin⁴², Lael M Yonker^{6

7

8}, E John Wherry³²

Affiliations

¹ PolyBio Research Foundation, Medford, MA, USA. aproal@polybio.org.
² PolyBio Research Foundation, Medford, MA, USA.
³ Division of Neurotherapeutics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Dept of Infectious Diseases and Unit of Post-Covid Huddinge, Karolinska University Hospital, Stockholm, Sweden.
⁵ Nonresident Senior Fellow, Brookings Institution, Washington, DC, USA.
⁶ Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.
⁷ Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA.
⁹ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.
¹⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, UPENN, Philadelphia, PA, USA.
¹¹ Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
¹² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Respiratory Medicine, University Hospital Llandough, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.
¹⁴ J. Craig Venter Institute, La Jolla, CA, USA.
¹⁵ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁶ Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease, Charlestown, MA, USA.
¹⁷ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
¹⁸ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ The Critical Illness, Brain Dysfunction, Survivorship (CIBS) Center at Vanderbilt University Medical Center and the Veteran's Affairs Tennessee Valley Geriatric Research Education Clinical Center (GRECC), Nashville, TN, USA.
²⁰ J. Craig Venter Institute Department of Infectious Diseases, University of California, San Diego, La Jolla, CA, USA.
²¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²² W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
²³ Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, USA.
²⁴ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
²⁵ Center for Infection and Immunity, Yale University School of Medicine, New Haven, CT, USA.
²⁶ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
²⁷ Department of Radiology, Harvard Medical School, Charlestown, MA, USA.
²⁸ Department of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁹ Institute for Immunology and Immune Health, and Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA, USA.
³⁰ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³¹ Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³² Institute for Immunology and Immune Health, and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School Medicine, Philadelphia, PA, USA.
³³ Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
³⁴ Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
³⁵ Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.
³⁶ Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.
³⁷ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁸ Department of Informatics, J. Craig Venter Institute, La Jolla, CA, USA.
³⁹ Department of Pathology, University of California, San Diego, San Diego, CA, USA.
⁴⁰ La Jolla Institute for Immunology, San Diego, CA, USA.
⁴¹ Division of Infectious Diseases, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁴² Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

PMID: 37667052
DOI: 10.1038/s41590-023-01601-2

Abstract

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.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents
COVID-19*
Disease Progression
Humans
Post-Acute COVID-19 Syndrome
RNA, Viral / genetics
SARS-CoV-2

Substances

RNA, Viral
Antiviral Agents

Grants and funding

K08 HL143183/HL/NHLBI NIH HHS/United States