Rapamycin adjuvant therapy did not improve the outcome of severe influenza virus infection in an experimental mouse model system

Abstract

The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. Severe influenza with morbidity and mortality is commonly believed to be the result of overwhelming immune response. In addition to antiviral agent, adjuvant therapy with immune modulating agent is a reasonable approach for severe influenza and has been reported to be effective in clinical series. As the immunity is also critical for virus eradication and recovery, we investigated to try to define the appropriate window for immune modulation in our murine animal model of influenza virus infection. Rapamycin treatment in a wide dose range did not alter the clinical course of severe influenza. In combination with antiviral agent Oseltamivir, rapamycin failed to offer additional benefit beyond treatment with Oseltamivir alone. Oseltamivir barely rescued the mice from severe influenza if the treatment was delayed until 48 hours after infection. Rapamycin did not provide salvage effect in this scenario. In fact, rapamycin suppressed influenza antigen specific CD4+ T cell response and impaired the virus eradication capacity. The virus burden in the lung increased with intense neutrophil infiltration and hyaline deposition in the alveoli. In conclusion, rapamycin cannot be relied upon as a salvage measure in severe influenza with progressive illness under treatment with Oseltamivir. T cell immunity is suppressed but other arms of immunity are recruited with undesirable effect on the disease outcome.