Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

doi:10.7554/eLife.86014

Review

. 2023 May 26:12:e86014.

doi: 10.7554/eLife.86014.

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

Sindhu Mohandas¹, Prasanna Jagannathan², Timothy J Henrich³, Zaki A Sherif⁴, Christian Bime⁵, Erin Quinlan⁶, Michael A Portman⁷, Marila Gennaro⁸, Jalees Rehman⁹; RECOVER Mechanistic Pathways Task Force

Collaborators, Affiliations

Collaborators

RECOVER Mechanistic Pathways Task Force:
Steven B Bradfute¹⁰, Benjamin K Chen¹¹, Thomas J Connors¹², K Coombs¹³, Christian R Gomez¹⁴, Boris D Julg¹⁵, C Kim¹³, W Brian Reeves¹⁶

Affiliations

¹ Division of Infectious Diseases, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, United States.
² Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, United States.
³ Division of Experimental Medicine, University of California, San Francisco, San Francisco, United States.
⁴ Department of Biochemistry & Molecular Biology, Howard University College of Medicine, Washington, United States.
⁵ Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, University of Arizona College of Medicine, Tucson, United States.
⁶ National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, United States.
⁷ Seattle Children's Hospital, Division of Pediatric Cardiology, Department of Pediatrics, University of Washington, Seattle, United States.
⁸ Public Health Research Institute and Department of Medicine, Rutgers New Jersey Medical School, Newark, United States.
⁹ Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, United States.
¹⁰ Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States.
¹¹ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States.
¹² Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's Hospital, New York, United States.
¹³ NIH RECOVER Research Initiative: Patient representative, Bethesda, United States.
¹⁴ Division of Lung Diseases, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, United States.
¹⁵ Infectious Disease Division, Massachusetts General Hospital, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States.
¹⁶ Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas San Antonio, San Antonio, United States.

PMID: 37233729
PMCID: PMC10219649
DOI: 10.7554/eLife.86014

Review

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

Sindhu Mohandas et al. Elife. 2023.

. 2023 May 26:12:e86014.

doi: 10.7554/eLife.86014.

Authors

Collaborators

RECOVER Mechanistic Pathways Task Force:
Steven B Bradfute¹⁰, Benjamin K Chen¹¹, Thomas J Connors¹², K Coombs¹³, Christian R Gomez¹⁴, Boris D Julg¹⁵, C Kim¹³, W Brian Reeves¹⁶

Affiliations

¹ Division of Infectious Diseases, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, United States.
² Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, United States.
³ Division of Experimental Medicine, University of California, San Francisco, San Francisco, United States.
⁴ Department of Biochemistry & Molecular Biology, Howard University College of Medicine, Washington, United States.
⁵ Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, University of Arizona College of Medicine, Tucson, United States.
⁶ National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, United States.
⁷ Seattle Children's Hospital, Division of Pediatric Cardiology, Department of Pediatrics, University of Washington, Seattle, United States.
⁸ Public Health Research Institute and Department of Medicine, Rutgers New Jersey Medical School, Newark, United States.
⁹ Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, United States.
¹⁰ Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, United States.
¹¹ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States.
¹² Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's Hospital, New York, United States.
¹³ NIH RECOVER Research Initiative: Patient representative, Bethesda, United States.
¹⁴ Division of Lung Diseases, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, United States.
¹⁵ Infectious Disease Division, Massachusetts General Hospital, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States.
¹⁶ Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas San Antonio, San Antonio, United States.

PMID: 37233729
PMCID: PMC10219649
DOI: 10.7554/eLife.86014

Abstract

With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.

Keywords: COVID-19; PASC; adaptive immunity; immunology; immunopathology; inflammation; innate immunity.

PubMed Disclaimer

Conflict of interest statement

SM, PJ, TH, ZS, CB, MP, MG, JR No competing interests declared, EQ is employed by the NIH which funded the RECOVER trial

Figures

**Figure 1.. A simplified overview of responses of the immune system to the SARS-CoV-2 virus, over various time courses that lead to severe COVID-19 and long COVID (PASC) in some patients.**
The innate immune response serves as the initial line of defense against the virus, involving the activation of immune cells such as monocytes, natural killer (NK) cells, dendritic cells, and macrophages. These cells release cytokines and chemokines to recruit other immune cells, such as T cells and neutrophils, to the site of infection. Later in the course of the infection, the adaptive immune cells including B plasma cells release antibodies. However, the overreactive immune responses trigger inflammatory conditions that are sustained in PASC due to dysregulation of the immune system. The diagram was created using the Biorender.com software.

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References

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[1] Afrin LB, Weinstock LB, Molderings GJ. Covid-19 Hyperinflammation and post-COVID-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases. 2020;100:327–332. doi: 10.1016/j.ijid.2020.09.016. - DOI - PMC - PubMed

[2] Afrin LB, Weinstock LB, Molderings GJ. Covid-19 Hyperinflammation and post-COVID-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases. 2020;100:327–332. doi: 10.1016/j.ijid.2020.09.016. - DOI - PMC - PubMed

[3] Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, Azizi G. Interleukin-6 cytokine: an overview of the immune regulation, immune dysregulation, and therapeutic approach. International Immunopharmacology. 2022;111:109130. doi: 10.1016/j.intimp.2022.109130. - DOI - PubMed

[4] Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, Azizi G. Interleukin-6 cytokine: an overview of the immune regulation, immune dysregulation, and therapeutic approach. International Immunopharmacology. 2022;111:109130. doi: 10.1016/j.intimp.2022.109130. - DOI - PubMed

[5] Aschenbrenner AC, Mouktaroudi M, Krämer B, Oestreich M, Antonakos N, Nuesch-Germano M, Gkizeli K, Bonaguro L, Reusch N, Baßler K, Saridaki M, Knoll R, Pecht T, Kapellos TS, Doulou S, Kröger C, Herbert M, Holsten L, Horne A, Gemünd ID, Rovina N, Agrawal S, Dahm K, van Uelft M, Drews A, Lenkeit L, Bruse N, Gerretsen J, Gierlich J, Becker M, Händler K, Kraut M, Theis H, Mengiste S, De Domenico E, Schulte-Schrepping J, Seep L, Raabe J, Hoffmeister C, ToVinh M, Keitel V, Rieke G, Talevi V, Skowasch D, Aziz NA, Pickkers P, van de Veerdonk FL, Netea MG, Schultze JL, Kox M, Breteler MMB, Nattermann J, Koutsoukou A, Giamarellos-Bourboulis EJ, Ulas T, German COVID-19 Omics Initiative DeCOI Disease severity-specific neutrophil signatures in blood Transcriptomes stratify COVID-19 patients. Genome Medicine. 2021;13:7. doi: 10.1186/s13073-020-00823-5. - DOI - PMC - PubMed

[6] Aschenbrenner AC, Mouktaroudi M, Krämer B, Oestreich M, Antonakos N, Nuesch-Germano M, Gkizeli K, Bonaguro L, Reusch N, Baßler K, Saridaki M, Knoll R, Pecht T, Kapellos TS, Doulou S, Kröger C, Herbert M, Holsten L, Horne A, Gemünd ID, Rovina N, Agrawal S, Dahm K, van Uelft M, Drews A, Lenkeit L, Bruse N, Gerretsen J, Gierlich J, Becker M, Händler K, Kraut M, Theis H, Mengiste S, De Domenico E, Schulte-Schrepping J, Seep L, Raabe J, Hoffmeister C, ToVinh M, Keitel V, Rieke G, Talevi V, Skowasch D, Aziz NA, Pickkers P, van de Veerdonk FL, Netea MG, Schultze JL, Kox M, Breteler MMB, Nattermann J, Koutsoukou A, Giamarellos-Bourboulis EJ, Ulas T, German COVID-19 Omics Initiative DeCOI Disease severity-specific neutrophil signatures in blood Transcriptomes stratify COVID-19 patients. Genome Medicine. 2021;13:7. doi: 10.1186/s13073-020-00823-5. - DOI - PMC - PubMed

[7] Bassler K, Schulte-Schrepping J, Warnat-Herresthal S, Aschenbrenner AC, Schultze JL. The myeloid cell compartment-cell by cell. Annual Review of Immunology. 2019;37:269–293. doi: 10.1146/annurev-immunol-042718-041728. - DOI - PubMed

[8] Bassler K, Schulte-Schrepping J, Warnat-Herresthal S, Aschenbrenner AC, Schultze JL. The myeloid cell compartment-cell by cell. Annual Review of Immunology. 2019;37:269–293. doi: 10.1146/annurev-immunol-042718-041728. - DOI - PubMed

[9] Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D’Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J, HGID Lab. NIAID-USUHS Immune Response to COVID Group. COVID Clinicians. COVID-STORM Clinicians. Imagine COVID Group. French COVID Cohort Study Group. Milieu Intérieur Consortium. CoV-Contact Cohort. Amsterdam UMC Covid-19 Biobank. COVID Human Genetic Effort. Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL. Autoantibodies against type I Ifns in patients with life-threatening COVID-19. Science. 2020;370:eabd4585. doi: 10.1126/science.abd4585. - DOI - PMC - PubMed

[10] Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D’Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J, HGID Lab. NIAID-USUHS Immune Response to COVID Group. COVID Clinicians. COVID-STORM Clinicians. Imagine COVID Group. French COVID Cohort Study Group. Milieu Intérieur Consortium. CoV-Contact Cohort. Amsterdam UMC Covid-19 Biobank. COVID Human Genetic Effort. Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL. Autoantibodies against type I Ifns in patients with life-threatening COVID-19. Science. 2020;370:eabd4585. doi: 10.1126/science.abd4585. - DOI - PMC - PubMed

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Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

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Affiliations

Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

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Conflict of interest statement

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