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Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection.
Silverstein, Noah J; Wang, Yetao; Manickas-Hill, Zachary; Carbone, Claudia; Dauphin, Ann; Boribong, Brittany P; Loiselle, Maggie; Davis, Jameson; Leonard, Maureen M; Kuri-Cervantes, Leticia; Meyer, Nuala J; Betts, Michael R; Li, Jonathan Z; Walker, Bruce D; Yu, Xu G; Yonker, Lael M; Luban, Jeremy.
  • Silverstein NJ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
  • Wang Y; Medical Scientist Training Program, University of Massachusetts Medical School, Worcester, United States.
  • Manickas-Hill Z; Massachusetts Consortium on Pathogen Readiness, Boston, United States.
  • Carbone C; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
  • Dauphin A; Massachusetts Consortium on Pathogen Readiness, Boston, United States.
  • Boribong BP; Massachusetts Consortium on Pathogen Readiness, Boston, United States.
  • Loiselle M; Ragon Institute of MGH, MIT and Harvard, Cambridge, United States.
  • Davis J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
  • Leonard MM; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
  • Kuri-Cervantes L; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States.
  • Meyer NJ; Harvard Medical School, Boston, United States.
  • Betts MR; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States.
  • Li JZ; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States.
  • Walker BD; Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, United States.
  • Yu XG; Massachusetts General Hospital, Department of Pediatrics, Boston, United States.
  • Yonker LM; Harvard Medical School, Boston, United States.
  • Luban J; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Elife ; 112022 03 11.
Article in English | MEDLINE | ID: covidwho-1742931
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Lymphopenia Type of study: Cohort study / Observational study / Prognostic study Topics: Long Covid Limits: Child / Female / Humans / Male Language: English Year: 2022 Document Type: Article Affiliation country: ELife.74681

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 / Lymphopenia Type of study: Cohort study / Observational study / Prognostic study Topics: Long Covid Limits: Child / Female / Humans / Male Language: English Year: 2022 Document Type: Article Affiliation country: ELife.74681