Dual roles for influenza A protein PA-X: limiting inflammatory response and disrupting MHC I antigen presentation in human respiratory epithelium

Key to the success of influenza A virus as a pathogen are its numerous tactics of immune evasion. To suppress anti-viral cellular and organismal responses, influenza A virus encodes several immunomodulatory proteins, including the endoribonuclease PA-X. PA-X decreases inflammation and immune responses in in vivo infections by limiting host gene expression. PA-X is conserved in 99% of all influenza A viral strains, pointing to its importance as a crucial immunomodulator. However, it is not yet known how PA-X activity alters the antiviral response in the human airway or how it benefits the virus. To define how influenza A virus uses this protein to evade immune responses, we characterized the impacts of PA-X on the host response to infection in the infected and bystander cells of the airway epithelium using a 3D ex vivo model. We discovered that PA-X exerts a dual action on immune responses, dampening aspects of both the innate and adaptive immune systems. Consistent with reports in model organisms, PA-X significantly decreases secretion of multiple cytokines from airway epithelium, including IFN-{lambda}, which likely plays a role in its ability to reduce inflammation and lung damage. In addition, we revealed that PA-X decreases and delays MHC I antigen presentation from infected cells. This reduction likely aids influenza A virus in hiding from antigen-specific T cells and allows the virus to successfully replicate prior to immune detection. This new function for PA-X highlights how influenza A virus employs active mechanisms to block immune detection, in addition to tolerating high levels of antigen mutations to escape it. Moreover, as evasion of recognition by the adaptive immune system is particularly important during infections of animals and humans with pre-existing immunity, this immunomodulatory activity may be key to the longevity of influenza A viruses and their continued circulation.