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

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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.

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COVID-19: consider cytokine storm syndromes and immunosuppression

Puja Mehta, Daniel McAuley, Michael Brown … (2020)

As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).

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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu … (2021)

Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

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The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Karen V. Swanson, Meng Deng, Jenny P.-Y. Ting (2019)

NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

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Author and article information

Contributors

Sindhu Mohandas:

ORCID: https://orcid.org/0000-0002-8397-6249

Jalees Rehman:

ORCID: https://orcid.org/0000-0002-2787-9292

Jameel Iqbal: Role: Reviewing Editor

Mone Zaidi: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 26 May 2023

Publication date Collection: 2023

Publication date PMC-release: 26 May 2023

Volume: 12

Electronic Location Identifier: e86014

Affiliations

Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center ( https://ror.org/02e5dc168) AlbuquerqueUnited States

Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai ( https://ror.org/04a9tmd77) New YorkUnited States

Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's Hospital ( https://ror.org/00hj8s172) New YorkUnited States

NIH RECOVER Research Initiative: Patient representative ( https://ror.org/01cwqze88) BethesdaUnited States

Division of Lung Diseases, National Institutes of Health, National Heart, Lung and Blood Institute ( https://ror.org/01cwqze88) BethesdaUnited States

Infectious Disease Division, Massachusetts General Hospital, Ragon Institute of MGH, MIT and Harvard ( https://ror.org/002pd6e78) CambridgeUnited States

NIH RECOVER Research Initiative: Patient representative ( https://ror.org/01cwqze88) BethesdaUnited States

Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas San Antonio ( https://ror.org/01kd65564) San AntonioUnited States

[1 ] Division of Infectious Diseases, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California ( https://ror.org/03taz7m60) Los Angeles United States

[2 ] Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University ( https://ror.org/00f54p054) Stanford United States

[3 ] Division of Experimental Medicine, University of California, San Francisco ( https://ror.org/043mz5j54) San Francisco United States

[4 ] Department of Biochemistry & Molecular Biology, Howard University College of Medicine ( https://ror.org/05gt1vc06) Washington United States

[5 ] Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, University of Arizona College of Medicine ( https://ror.org/03m2x1q45) Tucson United States

[6 ] National Center for Complementary and Integrative Health, National Institutes of Health ( https://ror.org/01cwqze88) Bethesda United States

[7 ] Seattle Children’s Hospital, Division of Pediatric Cardiology, Department of Pediatrics, University of Washington ( https://ror.org/00cvxb145) 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 ( https://ror.org/05e94g991) Chicago United States

DaVita Labs United States

Icahn School of Medicine at Mount Sinai ( https://ror.org/04a9tmd77) United States

Author information

Sindhu Mohandas https://orcid.org/0000-0002-8397-6249

Prasanna Jagannathan https://orcid.org/0000-0001-6305-758X

Zaki A Sherif https://orcid.org/0000-0002-1772-7041

Jalees Rehman https://orcid.org/0000-0002-2787-9292

Article

Publisher ID: 86014

DOI: 10.7554/eLife.86014

PMC ID: 10219649

PubMed ID: 37233729

SO-VID: 33d36c4b-d59e-4697-bbdf-990db2e88631

License:

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 09 January 2023

Date accepted : 18 May 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: OT2HL161847

Award Recipient : Sindhu Mohandas

The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement Immune dysregulation is thought to be a hallmark of long COVID or PASC but there is a need for understanding the underlying mechanisms which drive the disease progression.

ScienceOpen disciplines: Life sciences

Keywords: covid-19,pasc,immunopathology,innate immunity,adaptive immunity

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: covid-19, pasc, immunopathology, innate immunity, adaptive immunity