Rebalancing Viral and Immune Damage versus Tissue Repair Prevents Death from Lethal Influenza Infection

Maintaining tissue function while eliminating infected cells is fundamental to host defense. Innate inflammatory damage contributes to lethal influenza and COVID-19, yet other than steroids, immunomodulatory drugs have modest effects. Among more than 50 immunomodulatory regimes tested in mouse lethal influenza infection, only the previously reported early depletion of neutrophils showed efficacy, suggesting that the infected host passes an early tipping point in which limiting innate immune damage alone cannot rescue physiological function. To re-balance the system late in infection, we investigated whether partial limitation of viral spread using oseltamivir (Tamiflu) together with enhancement of epithelial repair by blockade of interferon signaling or the limitation of further epithelial cell loss mediated by cytotoxic CD8 ⁺ T cells would prevent death. These treatments salvaged 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 pulmonary infections.