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

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.

Human innate lymphoid cell activation by adenoviruses is modified by host defense proteins and neutralizing antibodies

“…When working with primary ILCs from multiple donors, the heterogeneity of the response is typically considerable. ILC levels in peripheral blood vary with age (up to 7-fold less in older adults compared to children), sex (less abundant in males), and whether responding to a viral infection ( 11 ). While our approach inherently creates challenges for broad interpretations, it nonetheless represents a sampling of the diverse human responses.…”

“…LTi (lymphoid tissue-inducer) cells belong the ILC3 subset and are involved in embryonic lymph node formation. Yet, ILC subsets are not static and show context-specific heterogeneity and plasticity, particularly as we age and during the development of antiviral responses ( 10 , 11 ).…”

Tissue-resident immunity in the lung: a first-line defense at the environmental interface

“…Higher expression of activation and homing markers in ILCs from infected individuals was associated with severe infection [168]. This finding together with decreased NK, ILC1 and ILC2 numbers in the blood of COVID-19 patients [169] suggest that ILCs migrate and persist in the lung upon severe infection.…”

Host cell stress response as a predictor of COVID-19 infectivity and disease progression

“…7 Role of heat shock proteins in inflammation SARS-CoVs cause ARDS (Reizine et al, 2021), hemophagocytic syndrome (Yang et al, 2021), lymphoid depletion (Silverstein et al, 2022) and skeletal muscle fibre necrosis (Suh et al, 2021), which are all consequences of elevated levels of pro-inflammatory cytokines.…”