Understanding long term consequences of respiratory viral infection 2260810

Abstract

In the wake of the SARS-CoV-2 pandemic, most people have experienced at least one respiratory viral infection and many endured severe disease, yet the long term immune consequences remain unclear. We hypothesized that severe infection episode durably reshapes circulating immunity and accelerates age-like change. To enable within-animal longitudinal inference, we focused on blood so the same mice could be profiled over time. Wild type mice received sublethal influenza A virus (IAV) or mock, and whole blood single-cell RNA-seq of PBMCs was performed at 2, 4, 8, and 14 months post infection from the same animals. Severe IAV was associated with a progressive rise in the neutrophil-to-lymphoid ratio (NLR) from 2-14 months versus mock, with concomitant declines in naïve B and T cells. A GZMK+ CD8 T-cell subset increased in frequency and activation state in infected mice. These features paralleled aging like myeloid bias programs, consistent with infection accelerated immunosenescence. Ongoing analyses use batch aware mixed effects models and gene set scoring to define cell-state programs linked to NLR and GZMK+ CD8 expansion. Our findings suggest that severe respiratory viral insult can imprint durable remodeling of circulating immunity, identifying the specific transcriptional signatures and upstream mediators may reveal targets to restore immune balance and resilience during age. n/a Viral Immunology (VIR)