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

Maintaining tissue function while eliminating pathogen-infected cells is a fundamental challenge in host defense. Studies of acute viral respiratory diseases such as influenza and COVID-19 have emphasized the key role of innate inflammatory damage survival on outcome, yet other than high dose steroids, a wide variety of immunomodulatory drugs have only modest positive effects. Here we tested more than 50 immunomodulatory regimes in a mouse model of lethal influenza infection, with only the previously reported early depletion of neutrophils showing efficacy. This suggests that the infected host passes an early tipping point in which reduction of further innate immune damage alone cannot rescue adequate physiological tissue function. To re-balance the system around this tipping point, we investigated whether late in infection, partial limitation of viral spread using oseltamivir (Tamiflu) together with enhancement of epithelial repair by blockade of interferon signaling or limitation of further epithelial cell loss mediated by cytotoxic CD8+ T cells would rescue infected animals. These treatments rescued a large fraction of infected animals through the two anticipated mechanisms. These findings provide new insight into the importance of repair processes and the timing of adaptive immune responses in survival from influenza infections.