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dc.contributor.authorSilverstein, Noah J.
dc.contributor.authorWang, Yetao
dc.contributor.authorManickas-Hill, Zachary
dc.contributor.authorCarbone, Claudia C.
dc.contributor.authorDauphin, Ann
dc.contributor.authorMGH COVID-19 Collection & Processing Team
dc.contributor.authorLi, Jonathan Z.
dc.contributor.authorWalker, Bruce D.
dc.contributor.authorYu, Xu G.
dc.contributor.authorLuban, Jeremy
dc.date2022-08-11T08:08:26.000
dc.date.accessioned2022-08-23T15:55:14Z
dc.date.available2022-08-23T15:55:14Z
dc.date.issued2021-01-15
dc.date.submitted2021-03-15
dc.identifier.citation<p>Silverstein NJ, Wang Y, Manickas-Hill Z, Carbone C, Dauphin A, Boribong BP, Loiselle M, Davis J, Leonard MM, Kuri-Cervantes L; MGH COVID-19 Collection & Processing Team, Meyer NJ, Betts MR, Li JZ, Walker B, Yu XG, Yonker LM, Luban J. Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection. medRxiv [Preprint]. 2021 Oct 11:2021.01.14.21249839. doi: 10.1101/2021.01.14.21249839. Update in: Elife. 2022 Mar 11;11: PMID: 33469605; PMCID: PMC7814851. <a href="https://doi.org/10.1101/2021.01.14.21249839" target="_blank" title="view preprint on medRxiv">Link to preprint on medRxiv</a></p>
dc.identifier.doi10.1101/2021.01.14.21249839
dc.identifier.pmid33469605
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29708
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p>
dc.description.abstractBACKGROUND: Risk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality. METHODS: Flow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40) and those treated as outpatients for less severe disease (n=51). 86 healthy individuals served as controls. The relationship between abundance of specific blood lymphoid cell types, age, sex, hospitalization, duration of hospitalization, and elevation of blood markers for systemic inflammation, was determined using multiple regression. RESULTS: After accounting for effects of age and sex, hospitalization for COVID-19 was associated with 1.78-fold fewer ILCs (95%CI: 2.34–1.36; p = 4.55 x 10−5) and 2.31-fold fewer CD16+ natural killer (NK) cells (95%CI: 3.1–1.71; p = 1.04 x 10−7), when compared to uninfected controls. Among people infected with SARS-CoV-2, the odds ratio for hospitalization, adjusted for age, sex, and duration of symptoms, was 0.413 (95%CI: 0.197–0.724; p = 0.00691) for every 2-fold increase in ILCs. In addition, higher ILC abundance was associated with less time spent in the hospital and lower levels of blood markers associated with COVID-19 severity: each two-fold increase in ILC abundance was associated with a 9.38 day decrease in duration of hospital stay (95% CI: 15.76–3.01; p= 0.0054), and decrease in blood C-reactive protein (CRP) by 46.29 mg/L (95% CI: 71.34–21.24; p = 6.25 x 10−4), erythrocyte sedimentation rate (ESR) by 11.04 mm/h (95% CI: 21.94–0.13; p = 0.047), and the fibrin degradation product D-dimer by 1098.52 ng/mL (95% CI: 1932.84–264.19; p = 0.011). CONCLUSIONS: Both ILCs and NK cells were depleted in the blood of people hospitalized for severe COVID-19, but, among lymphoid cell subsets, only ILC abundance was independently associated with the need for hospitalization, duration of hospital stay, and severity of inflammation. These results indicate that, by promoting disease tolerance, homeostatic ILCs protect against morbidity and mortality in SARS-CoV-2 infection, and suggest that reduction in the number of ILCs with age and in males accounts for the increased risk of severe COVID-19 in these demographic groups.
dc.language.isoen_US
dc.relationNow published in eLife doi: 10.7554/eLife.74681
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectInfectious Diseases
dc.subjectCOVID-19
dc.subjectSARS-CoV-2 infection
dc.subjectage
dc.subjectsex
dc.subjectmorbidity
dc.subjectmortality
dc.subjectseverity
dc.subjectblood lymphoid cells
dc.subjectEpidemiology
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectImmunopathology
dc.subjectInfectious Disease
dc.subjectVirology
dc.subjectVirus Diseases
dc.titleInnate lymphoid cells and disease tolerance in SARS-CoV-2 infection [preprint]
dc.typePreprint
dc.source.journaltitlemedRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2942&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1921
dc.identifier.contextkey22062488
refterms.dateFOA2022-08-23T15:55:14Z
html.description.abstract<p><p id="x-x-x-p-3">BACKGROUND: Risk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality. <p id="x-x-x-p-4">METHODS: Flow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40) and those treated as outpatients for less severe disease (n=51). 86 healthy individuals served as controls. The relationship between abundance of specific blood lymphoid cell types, age, sex, hospitalization, duration of hospitalization, and elevation of blood markers for systemic inflammation, was determined using multiple regression. <p id="x-x-x-p-5">RESULTS: After accounting for effects of age and sex, hospitalization for COVID-19 was associated with 1.78-fold fewer ILCs (95%CI: 2.34–1.36; p = 4.55 x 10<sup>−5</sup>) and 2.31-fold fewer CD16<sup>+</sup> natural killer (NK) cells (95%CI: 3.1–1.71; p = 1.04 x 10<sup>−7</sup>), when compared to uninfected controls. Among people infected with SARS-CoV-2, the odds ratio for hospitalization, adjusted for age, sex, and duration of symptoms, was 0.413 (95%CI: 0.197–0.724; p = 0.00691) for every 2-fold increase in ILCs. In addition, higher ILC abundance was associated with less time spent in the hospital and lower levels of blood markers associated with COVID-19 severity: each two-fold increase in ILC abundance was associated with a 9.38 day decrease in duration of hospital stay (95% CI: 15.76–3.01; p= 0.0054), and decrease in blood C-reactive protein (CRP) by 46.29 mg/L (95% CI: 71.34–21.24; p = 6.25 x 10<sup>−4</sup>), erythrocyte sedimentation rate (ESR) by 11.04 mm/h (95% CI: 21.94–0.13; p = 0.047), and the fibrin degradation product D-dimer by 1098.52 ng/mL (95% CI: 1932.84–264.19; p = 0.011). <p id="x-x-x-p-6">CONCLUSIONS: Both ILCs and NK cells were depleted in the blood of people hospitalized for severe COVID-19, but, among lymphoid cell subsets, only ILC abundance was independently associated with the need for hospitalization, duration of hospital stay, and severity of inflammation. These results indicate that, by promoting disease tolerance, homeostatic ILCs protect against morbidity and mortality in SARS-CoV-2 infection, and suggest that reduction in the number of ILCs with age and in males accounts for the increased risk of severe COVID-19 in these demographic groups.</p>
dc.identifier.submissionpathfaculty_pubs/1921
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentGraduate School of Biomedical Sciences, MD/PhD Program
dc.contributor.departmentMedical Scientist Training Program
dc.contributor.departmentProgram in Molecular Medicine


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The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.