Review

. 2023 Oct;24(10):1616-1627.

doi: 10.1038/s41590-023-01601-2. Epub 2023 Sep 4.

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

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

Review

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

Amy D Proal et al. Nat Immunol. 2023 Oct.

. 2023 Oct;24(10):1616-1627.

doi: 10.1038/s41590-023-01601-2. Epub 2023 Sep 4.

Authors

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

Erratum in

Author Correction: SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC).
Proal AD, VanElzakker MB, Aleman S, Bach K, Boribong BP, Buggert M, Cherry S, Chertow DS, Davies HE, Dupont CL, Deeks SG, Eimer W, Ely EW, Fasano A, Freire M, Geng LN, Griffin DE, Henrich TJ, Iwasaki A, Izquierdo-Garcia D, Locci M, Mehandru S, Painter MM, Peluso MJ, Pretorius E, Price DA, Putrino D, Scheuermann RH, Tan GS, Tanzi RE, VanBrocklin HF, Yonker LM, Wherry EJ. Proal AD, et al. Nat Immunol. 2023 Oct;24(10):1778. doi: 10.1038/s41590-023-01646-3. Nat Immunol. 2023. PMID: 37723351 No abstract available.

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.

PubMed Disclaimer

Cited by

Microbes and Mental Illness: Past, Present, and Future.
Bransfield RC, Mao C, Greenberg R. Bransfield RC, et al. Healthcare (Basel). 2023 Dec 29;12(1):83. doi: 10.3390/healthcare12010083. Healthcare (Basel). 2023. PMID: 38200989 Free PMC article. Review.
A latent transfer learning method for estimating hospital-specific post-acute healthcare demands following SARS-CoV-2 infection.
Wu Q, Pajor NM, Lu Y, Wolock CJ, Tong J, Lorman V, Johnson KB, Moore JH, Forrest CB, Asch DA, Chen Y. Wu Q, et al. Patterns (N Y). 2024 Oct 24;5(11):101079. doi: 10.1016/j.patter.2024.101079. eCollection 2024 Nov 8. Patterns (N Y). 2024. PMID: 39568467 Free PMC article.
Replication-incompetent VSV-based vaccine elicits protective responses against SARS-CoV-2 and influenza virus.
Adeleke RA, Sahler J, Choi A, Roth K, Upadhye V, Ezzatpour S, Imbiakha B, Khomandiak S, Diaz A, Whittaker GR, Jager MC, August A, Buchholz DW, Aguilar HC. Adeleke RA, et al. Sci Adv. 2025 Jan 31;11(5):eadq4545. doi: 10.1126/sciadv.adq4545. Epub 2025 Jan 29. Sci Adv. 2025. PMID: 39879304 Free PMC article.
Emerging SARS-CoV-2 Resistance After Antiviral Treatment.
Tamura TJ, Choudhary MC, Deo R, Yousuf F, Gomez AN, Edelstein GE, Boucau J, Glover OT, Barry M, Gilbert RF, Reynolds Z, Li Y, Tien D, Vyas TD, Passell E, Su K, Drapkin S, Abar EG, Kawano Y, Sparks JA, Wallace ZS, Vyas JM, Shafer RW, Siedner MJ, Barczak AK, Lemieux JE, Li JZ; POSITIVES Study Team. Tamura TJ, et al. JAMA Netw Open. 2024 Sep 3;7(9):e2435431. doi: 10.1001/jamanetworkopen.2024.35431. JAMA Netw Open. 2024. PMID: 39320890 Free PMC article.
High prevalence of long COVID in anti-TPO positive euthyroid individuals with strongly elevated SARS-CoV-2-specific T cell responses and moderately raised anti-spike IgG levels 23 months post-infection.
Matula Z, Király V, Bekő G, Gönczi M, Zóka A, Steinhauser R, Uher F, Vályi-Nagy I. Matula Z, et al. Front Immunol. 2024 Oct 10;15:1448659. doi: 10.3389/fimmu.2024.1448659. eCollection 2024. Front Immunol. 2024. PMID: 39450181 Free PMC article.

See all "Cited by" articles

References

1. Proal, A. D. & VanElzakker, M. B. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front. Microbiol. https://doi.org/10.3389/FMICB.2021.698169 (2021).
1. National Center for Health Statistics. US Census Bureau, Household Pulse Survey, 2022–2023. Long COVID (2023).
1. Cutler, D. M. The economic cost of long COVID: an update (2023). White Paper. https://scholar.harvard.edu/files/cutler/files/long_covid_update_7-22.pdf (2023).
1. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. https://doi.org/10.1038/S41579-022-00846-2 (2023).
1. Davis, H. E. et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine https://doi.org/10.1016/J.ECLINM.2021.101019 (2021).

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Erratum in

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous