Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection

Abstract

BACKGROUNDRisk 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.METHODSFlow 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.RESULTSAfter 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).CONCLUSIONSBoth 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.

Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in older adults

“…[28] Furthermore, innate immunity has been found to play an important role in the control of infection in coronavirus animal reservoirs and may similarly contribute to reduced severity of COVID-19 disease observed in children compared to adults. [29,30] Our study found a durable reduction in the risk of COVID-19 infection following receipt of RZV vaccine, consistent with the durable protection against heterologous infections provided by trained immunity. [9] It is possible that the AS01 adjuvant used in RZV, which activates innate immune responses including monocytes and the IFN-response pathways, may be associated with the reduced risk of COVID-19 diagnosis and hospitalization observed in this study.…”

“…[28] Furthermore, innate immunity has been found to play an important role in the control of infection in coronavirus animal reservoirs and may similarly contribute to reduced severity of COVID-19 disease observed in children compared to adults. [29, 30]…”

Regulation and Function of ILC3s in Pulmonary Infections

“…Silverstein et al corroborate these findings by establishing that a higher ILC abundance in the blood was associated with less time spent in the hospital. Further, hospitalized individuals with COVID-19 had 1.78-fold fewer ILCs in the blood (78). Taken together, these studies illustrate a correlation between decreased ILCs in the blood periphery and severe SARS-CoV-2 infection.…”

Innate and Adaptive Immune Assessment at Admission to Predict Clinical Outcome in COVID-19 Patients

“…The role of total ILCs and specifically ILC1 in antiviral immune response has been previously shown [ 34 , 35 ]. A reduction of ILC1 in severe COVID-19 patients has been recently described by García et al [ 35 ].…”