Dual effects of influenza A virus PA-X on suppression of cytokine signaling and MHC I pathway disruption in the human airway epithelium

Abstract

The mechanisms of immune evasion of influenza A virus are key to its success as an infectious agent. To replicate effectively, influenza A virus must suppress both early innate immune responses, like antiviral type I and III interferons, and adaptive immune responses. The latter is particularly important during infections of animals and humans with pre-existing immunity and explains the continued circulation of influenza A viruses. Here we report how influenza A virus employes a single immunomodulatory protein, the endoribonuclease PA-X, to modulate both arms of the immune responses. To define how influenza A virus uses PA-X to evade immune responses, we characterized its impact on the host response to infection in the infected and bystander cells of the airway epithelium using a 3D ex vivo model and primary cells from multiple human donors. PA- X significantly decreases secretion of multiple cytokines from the airway epithelium, including IFN- {lambda}, inflammatory cytokines, and growth factors related to lung damage, which likely plays a role in its ability to modulate inflammation and lung pathology in vivo. In addition, we discovered that PA-X also decreases surface levels of major histocompatibility complex I (MHC I) on infected cells. This reduction may impact antigen-specific T cells and reduce adaptive immune detection. These dual functions for PA-X highlight how influenza A virus employs active mechanisms to block not only innate immunity but also adaptive immune detection, in addition to tolerating high levels of antigen mutations to escape it. Author SummaryInfluenza viruses must evade both innate and adaptive immune responses to infect, replicate, and transmit to new hosts. Through innate immunity, infected cells activate proteins to disrupt viral replication and alert surrounding cells. Through adaptive immunity, antigen-specific T cells recognize specific viral peptides and kill infected cells. We studied how influenza overcomes immune responses. Using a model of human airway tissue, we found a single influenza protein PA-X, can impinge on both innate and adaptive responses. PA-X decreases innate immune signaling between infected and surrounding cells and interferes with the major histocompatibility class I antigen presentation pathway. These dual functions allow PA-X to help the virus continue to circulate and infect new hosts, even in populations with immunity to the flu.