Harnessing the power of trained immunity in disease tolerance against influenza virus

Despite the world-wide application of vaccination and other anti-viral interventions, influenza infection remains a persistent threat to human health. The 1918 "Spanish" influenza pandemic killed approximately 40 million people in just one year. Similar to human infection, mouse models of the highly pathogenic 1918 strains have revealed that excessive inflammatory responses lead to lung injury/dysfunction and mortality. Therefore, understanding the severe pathology associated with highly virulent influenza viruses is a matter of urgency as further underscored by the recent pandemic of H1N1 influenza A. In fact, most influenza related deaths result from an unregulated host immune response to the virus rather than the cytopathic effects of the virus itself. Thus, it can be argued that the influenza virus is not the main threat; rather, it is the host's own immune-inflammatory response that jeopardizes host survival. How the immune system becomes dysregulated to the point of causing such massive immunopathology is currently not well understood. In this application, we aim to identify the molecular mechanisms involved in influenza virus induced pulmonary injury that will allow us to develop novel host-directed therapeutic strategies against influenza virus infection.