Brandolino, C. | bioRxiv Science

bioRxiv2026

Adaptive immune responses to vaccination reflect social status at first exposure in female rhesus macaques

Social gradients are consistently associated with variation in health outcomes, including infectious disease. However, distinguishing between social gradients in antigen exposure versus social gradients in susceptibility remains challenging. Here, we use a nonhuman primate model for chronic social stress to investigate how social status affects the influenza vaccine-induced adaptive immune response. We first manipulated the social status of female rhesus macaques and then tested the response to influenza antigens in naive individuals and after secondary exposure. Higher social status at the time of first exposure, but not at the time of secondary exposure, predicted stronger antibody responses to both exposures. Social status also drove gene expression differences in adaptive immune pathways, and genes that predicted the magnitude of the antibody response overlapped with those linked to social status. Thus, social gradients shape the adaptive immune response in a temporally dependent manner, with particular sensitivity at the time of initial antigen exposure.

genomics↗

bioRxiv2024

Widespread gene-environment interactions shape the immune response to SARS-CoV-2 infection in hospitalized COVID-19 patients

Genome-wide association studies performed in patients with coronavirus disease 2019 (COVID-19) have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. However, the underlying cis-regulatory genetic factors that contribute to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we used single-cell RNA-sequencing to quantify genetic contributions to cis-regulatory variation in 361,119 peripheral blood mononuclear cells across 63 COVID-19 patients during acute infection, 39 samples collected in the convalescent phase, and 106 healthy controls. Expression quantitative trait loci (eQTL) mapping across cell types within each disease state group revealed thousands of cis-associated variants, of which hundreds were detected exclusively in immune cells derived from acute COVID-19 patients. Patient-specific genetic effects dissipated as infection resolved, suggesting that distinct gene regulatory networks are at play in the active infection state. Further, 17.2% of tested loci demonstrated significant cell state interactions with genotype, with pathways related to interferon responses and oxidative phosphorylation showing pronounced cell state-dependent variation, predominantly in CD14+ monocytes. Overall, we estimate that 25.6% of tested genes exhibit gene-environment interaction effects, highlighting the importance of environmental modifiers in the transcriptional regulation of the immune response to SARS-CoV-2. Our findings underscore the importance of expanding the study of regulatory variation to relevant cell types and disease contexts and argue for the existence of extensive gene-environment effects among patients responding to an infection.

genomics↗