Work

Rebalancing viral and inflammatory damage versus tissue repair prevents death from lethal influenza infection 2480

Year: 2025

Type: article

Abstract: Description Maintaining tissue function while eliminating infected cells is a fundamental challenge to host defense. Innate inflammatory damage contributes to lethal influenza and COVID-19, yet other than steroids, immunomodulatory drugs have modest effects and delayed use of antivirals significantly dampens their efficacy. In this study we aimed to identify treatment strategies to prevent death from lethal influenza infection when antiviral treatment is suboptimal due to delayed dosing. However, use of more than 50 immunomodulatory reagents directed against innate inflammation failed to prevent death in infected mice. These data along with transcriptomic and tissue imaging studies led to a “tipping point” model in which early innate immune damage in the context of continued viral damage and late adaptive immunopathology leads to loss of viability. We hypothesized that rebalancing this system to maintain pulmonary function by either promoting the repair response or inhibiting late adaptive, not innate, tissue damage would enable survival. Here we report that limiting viral spread using oseltamivir (Tamiflu) in combination with enhancement of epithelial repair by blockade of type I interferon signaling or limitation of further epithelial cell loss mediated by cytotoxic CD8+ T cells rescued a large fraction of infected animals, providing new insight into the importance of repair processes and the timing of adaptive immune responses in survival of severe pulmonary infections. Funding Sources This work was supported by the Division of Intramural Research of NIAID, NIH. Topic Categories Viral Immunology (VIR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.392