Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection
- University of Massachusetts Medical School, United States
- Ragon Institute of MGH, MIT and Harvard, United States
- Massachusetts General Hospital, United States
- University of Pennsylvania, United States
- Brigham and Women's Hospital, United States
- 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.
-
Systematic analysis of innate lymphoid cells and natural killer cells in context of HIV-1 infectionNCBI Gene Expression Omnibus, GSE168212.
-
Group 3 innate lymphoid cells mediate early protective immunity against Mycobacterium tuberculosisNCBI Gene Expression Omnibus, GSE131031.
-
Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue SpecificityNCBI Gene Expression Omnibus, GSE126107.
Article and author information
Author details
Noah J Silverstein
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.
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.
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.
Metrics
-
- 2,296
- views
-
- 413
- downloads
-
- 41
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection
eLife 11:e74681.
https://doi.org/10.7554/eLife.74681
Further reading
-
- Immunology and Inflammation
Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of ‘younger’ microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.
-
- Immunology and Inflammation
As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
