Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection

  1. Noah J Silverstein
  2. Yetao Wang  Is a corresponding author
  3. Zachary Manickas-Hill
  4. Claudia Carbone
  5. Ann Dauphin
  6. Brittany P Boribong
  7. Maggie Loiselle
  8. Jameson Davis
  9. Maureen M Leonard
  10. Leticia Kuri-Cervantes
  11. MGH COVID-19 Collection & Processing Team
  12. Nuala J Meyer
  13. Michael R Betts
  14. Jonathan Z Li
  15. Bruce D Walker
  16. Xu G Yu
  17. Lael M Yonker
  18. Jeremy Luban  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. Ragon Institute of MGH, MIT and Harvard, United States
  3. Massachusetts General Hospital, United States
  4. University of Pennsylvania, United States
  5. Brigham and Women's Hospital, United States
  6. Ragon Institute of MGH, MIT, and Harvard, United States

Abstract

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations.

Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n=40), treated for COVID-19 as outpatients (n=51), and in uninfected controls (n=86), as well as in children with COVID-19 (n=19), recovering from COVID-19 (n=14), MIS-C (n=11), recovering from MIS-C (n=7), and pediatric controls (n=17).

Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls.

Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males.

Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.

Data availability

All clinical and flow cytometry data generated and analyzed in this article are included in the manuscript and are provided in three spreadsheets titled: "Adult_COVIDandControl_data.xlsx", "Pediatric_ COVID_MISC_andControl_data.xlsx", and "AREG_in_ILCs.xlsx". New Bulk RNA-seq datasets generated here are deposited at: NCBI Gene Expression Omnibus (GEO): GSE168212.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Noah J Silverstein

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5688-9978
  2. Yetao Wang

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    yetao.wang@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
  3. Zachary Manickas-Hill

    Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Claudia Carbone

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ann Dauphin

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Brittany P Boribong

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Maggie Loiselle

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1051-2072
  8. Jameson Davis

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Maureen M Leonard

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Leticia Kuri-Cervantes

    Institute for Immunology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. MGH COVID-19 Collection & Processing Team

  12. Nuala J Meyer

    Department of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Michael R Betts

    Institute for Immunology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Jonathan Z Li

    Department of Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Bruce D Walker

    Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Xu G Yu

    Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Lael M Yonker

    Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Jeremy Luban

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    jeremy.luban@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5650-4054

Funding

National Institutes of Health (R37AI147868)

  • Jeremy Luban

National Institutes of Health (R01AI148784)

  • Jeremy Luban

National Institutes of Health (F30HD100110)

  • Noah J Silverstein

National Institutes of Health (5K08HL143183)

  • Lael M Yonker

Massachusetts Consortium for Pathogen Readiness

  • Jeremy Luban

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

Reviewing Editor

  1. Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece

Ethics

Human subjects: As part of a COVID-19 observational study, peripheral blood samples were collected between March 31st and June 3rd of 2020 from 91 adults with SARS-CoV-2 infection, either after admission to Massachusetts General Hospital for the hospitalized cohort, or while at affiliated outpatient clinics for the outpatient cohort. Request for access to coded patient samples was reviewed by the Massachusetts Consortium for Pathogen Readiness (https://masscpr.hms.harvard.edu/) and approved by the University of Massachusetts Medical School IRB (protocol #H00020836). Pediatric participants with COVID-19 or MIS-C were enrolled in the Massachusetts General Hospital Pediatric COVID-19 Biorepository (MGB IRB # 2020P000955). Healthy pediatric controls were enrolled in the Pediatric Biorepository (MGB IRB # 2016P000949). Samples were collected after obtaining consent from the patient if 18 years or older, or from the parent/guardian, plus assent when appropriate.

Version history

  1. Preprint posted: January 15, 2021 (view preprint)
  2. Received: October 14, 2021
  3. Accepted: March 11, 2022
  4. Accepted Manuscript published: March 11, 2022 (version 1)
  5. Version of Record published: April 25, 2022 (version 2)

Copyright

© 2022, Silverstein et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Noah J Silverstein
  2. Yetao Wang
  3. Zachary Manickas-Hill
  4. Claudia Carbone
  5. Ann Dauphin
  6. Brittany P Boribong
  7. Maggie Loiselle
  8. Jameson Davis
  9. Maureen M Leonard
  10. Leticia Kuri-Cervantes
  11. MGH COVID-19 Collection & Processing Team
  12. Nuala J Meyer
  13. Michael R Betts
  14. Jonathan Z Li
  15. Bruce D Walker
  16. Xu G Yu
  17. Lael M Yonker
  18. Jeremy Luban
(2022)
Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection
eLife 11:e74681.
https://doi.org/10.7554/eLife.74681

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https://doi.org/10.7554/eLife.74681

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