The amazing innate immune response to influenza A virus infection.

Influenza A viruses (IAVs) remain a major health threat and a prime example of the significance of innate immunity. Our understanding of innate immunity to IAV has grown dramatically, yielding new concepts that change the way we view innate immunity as a whole. Examples include the role of p53, autophagy, microRNA, innate lymphocytes, endothelial cells and gut commensal bacteria in pulmonary innate immunity. Although the innate response is largely beneficial, it also contributes to major complications of IAV, including lung injury, bacterial super-infection and exacerbation of reactive airways disease. Research is beginning to dissect out which components of the innate response are helpful or harmful. IAV uses its limited genetic complement to maximum effect. Several viral proteins are dedicated to combating innate responses, while other viral structural or replication proteins multitask as host immune modulators. Many host innate immune proteins also multitask, having roles in cell cycle, signaling or normal lung biology. We summarize the plethora of new findings and attempt to integrate them into the larger picture of how humans have adapted to the threat posed by this remarkable virus. We explore how our expanded knowledge suggests ways to modulate helpful and harmful inflammatory responses, and develop novel treatments.