The Immunological Factors Predisposing To Severe COVID-19 Are Already Present In Healthy Elderly And Men

BackgroundMale sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. Given the seasonal profile of COVID-19, the seasonal response against SARS-CoV-2 could also be different in these groups. MethodsThe abundance of circulating proteins and immune populations associated with severe COVID-19 was analyzed in 2 healthy cohorts. PBMCs of female, male, young, and old subjects in different seasons of the year were stimulated with heat-inactivated SARS-CoV-2. ResultSeveral T cell subsets, which are known to be depleted in severe COVID-19 patients, were intrinsically less abundant in men and older individuals. Plasma proteins increasing with disease severity, including HGF, IL-8, and MCP-1, were more abundant in the elderly and males. The elderly produced significantly more IL-1RA and had a dysregulated IFN{gamma} response with lower production in the summer compared with young individuals. ConclusionsThe immune characteristics of severe COVID-19, described by a differential abundance of immune cells and circulating inflammatory proteins, are intrinsically present in healthy men and the elderly. This might explain the susceptibility of men and the elderly to SARS-CoV-2 infection. SummaryImmunological profile of severe COVID-19, characterized by altered immune cell populations and inflammatory plasma proteins is intrinsically present in healthy men and the elderly. Different age and sex groups show distinct seasonal responses to SARS-CoV-2.

A functional genomics approach to understand host genetic regulation ofCOVID-19 severity

Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity (1). Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Projects (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with increased susceptibility for severe disease in individuals with defective monocyte-derived cytokine production; ii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy. One Sentence summaryIn this study, we explore the physiological significance of the genetic variants associated with COVID-19 severity using detailed clinical, immunological and multi-omics data from large cohorts. Our findings allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.