Modulation of innate immune responses by the influenza A NS1 and PA-X proteins

Influenza A viruses (IAV) can infect a broad range of animal hosts, including humans. In humans, IAV causes seasonal annual epidemics and occasional pandemics, representing a serious public health and economic problem, which is most effectively prevented through vaccination. The defense mechanisms that the host innate immune system provides restrict IAV replication and infection. Consequently, to successfully replicate in interferon (IFN)-competent systems, IAV has to counteract host antiviral activities, mainly the production of IFN and the activities of IFN-induced host proteins that inhibit virus replication. The IAV multifunctional proteins PA-X and NS1 are virulence factors that modulate the innate immune response and virus pathogenicity. Notably, these two viral proteins have synergistic effects in the inhibition of host protein synthesis in infected cells, although using different mechanisms of action. Moreover, the control of innate immune responses by the IAV NS1 and PA-X proteins is subject to a balance that can determine virus pathogenesis and fitness, and recent evidence shows co-evolution of these proteins in seasonal viruses, indicating that they should be monitored for enhanced virulence. Importantly, inhibition of host gene expression by the influenza NS1 and/or PA-X proteins could be explored to develop improved live-attenuated influenza vaccines (LAIV) by modulating the ability of the virus to counteract antiviral host responses. Likewise, both viral proteins represent a reasonable target for the development of new antivirals for the control of IAV infections. In this review, we summarize the role of IAV NS1 and PA-X in controlling the antiviral response during viral infection.Influenza virus research in the Luis Mart í nez-Sobrido and David J. Topham laboratories is partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institutes of Health (NIH), and the Department of Health and Human Services under the Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract No. HHSN272201400005C (New York Influenza Center of Excellence, NYICE); by the Department of Defense (DoD) PR17046 (Luis Martinez-Sobrido); and with funds from a University of Rochester Research Award to Aitor Nogales and Marta Lopez de Diego. We also give thanks for the funds from Comunidad de Madrid, Spain, reference 2017-T1/BMD-5155 (Marta Lopez de Diego).Peer reviewe