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

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    Evaluation Summary:

    The authors present an interesting approach of COVID-19 pathogenesis with emphasis on the role of innate lymphoid cells as a major correlate of the severity of COVID-19 and of the levels of inflammatory markers. The main strength of the manuscript is the novelty of approach, and the fact that the authors are the first to find this potentially interesting correlation, which brings up a number of both translational and mechanistic possibilities of significance. The limitation, of course, is the difficulty in showing a cause-and-effect relationship between the reduction in of innate lymphoid cells and the severity of COVID-19 inflammation.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

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Abstract

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.

Article activity feed

  1. Evaluation Summary:

    The authors present an interesting approach of COVID-19 pathogenesis with emphasis on the role of innate lymphoid cells as a major correlate of the severity of COVID-19 and of the levels of inflammatory markers. The main strength of the manuscript is the novelty of approach, and the fact that the authors are the first to find this potentially interesting correlation, which brings up a number of both translational and mechanistic possibilities of significance. The limitation, of course, is the difficulty in showing a cause-and-effect relationship between the reduction in of innate lymphoid cells and the severity of COVID-19 inflammation.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. …

  2. Reviewer #1 (Public Review):

    The authors present an interesting approach of COVID-19 pathogenesis with emphasis on the role of innate lymphoid cells as the main driver of lymphopenia in severe COVID-19.

    The main strength of the manuscript is the novelty of approach being the first on that field. The main weaknesses are the difficulty in showing that the depletion of innate lymphoid cells is culprit for the lymphopenia of severe COVID-19 and of the subsequent hypoglobulinemia and the lack of further information on cytokine production capacity from these cells.

  3. Reviewer #2 (Public Review):

    In this manuscript the authors describe very rationally the hypothesis of association of ILC with age- and sex-dependent COVID-19 severity and moreover, through a series of well-designed experiments in both adults and children justify such a link. The manuscript is of great interest and the authors are to be congratulated for their meticulous approach. I only have some minor comments as follows. The authors should clarify when exactly blood sampling took place (at admission? during hospitalization? Before any treatment start?) as in Table 1 median duration of symptoms is about 20 days, quiet a long period; normally patients are admitted after the first week. If not at admission administered therapy especially corticosteroids may influence flow cytometry results. If therapy was administered this has to be …

  4. Reviewer #3 (Public Review):

    This study investigates the association between age, sex, the frequency of specific blood lymphocyte subsets, and COVID disease severity. In uninfected controls, they show a very clear link between age and changing lymphocyte frequencies in blood. This reveals a strong association between age and the frequency of total ILCs in blood and of so-called ILC-precursors (ILCp), which are highest at birth and decrease approximately twofold every 20 years. In addition, CD4 and CD8 T-cells were significantly lower in the oldest age category, while CD16+ NK cells appeared to increase with age. The authors also reveal a lower frequency of circulating ILCs in males than females, although the ranges are highly overlapping and the effect is weakly significant. By contrast, the lower CD4 count in males is striking and …

  5. SciScore for 10.1101/2021.01.14.21249839: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Cell subsets were identified using FlowJo™ software (Becton, Dickson and Company).
    FlowJo™
    suggested: (FlowJo, RRID:SCR_008520)
    STATISTICAL ANALYSIS AND DATA VISUALIZATION: Data were prepared for analysis with the tidyverse56 package, and visualized using the ggplot257 and ggpubr58 packages, within the R computer software environment
    R computer
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open …