Regulation of the cellular p53 protein by the influenza non-structural 1 (NS1) protein

The influenza A virus is a significant human pathogen, causing widespread disease and significant loss of life during yearly epidemics and occasional pandemics. The influenza A non-structural protein (NS1) is considered to be a critical regulator of cellular antiviral responses, because of its roles as an interferon antagonist and inhibitor of apoptosis. Influenza viruses are known to induce apoptosis during infection, both in vitro and in vivo. One key signaling protein involved in the induction of apoptosis and in antiviral signaling is the tumor suppressor protein p53. Our studies demonstrated that the inhibition of p53 during influenza virus infection results in increased viral replication, decreased apoptosis, and decreased interferon expression. This indicates that p53 plays a critical role in suppressing influenza virus replication and modulates the host response. We hypothesized that the NS1 protein may function to counteract the p53-mediated antiviral response. We determined that NS1 was necessary and sufficient to inhibit p53 during influenza infection. Our data indicates that NS1 binds to p53 to suppress the DNA binding activity, thereby inhibiting p53 transcriptional activity.;These studies clearly demonstrate the importance of p53 in vitro for preventing influenza virus replication. We also examined the role of p53 in the host response to influenza virus infection by inhibiting expression of p53 in a murine model. We determined that p53 plays a crucial role in the antiviral response, regulating influenza virus replication and disease-associated pathology. When p53 was inhibited in vivo, viral replication was higher in the lungs and also spread to peripheral organs, indicating a systemic infection. Morbidity and mortality was higher in mice with reduced expression of p53, and levels of pro-inflammatory cytokines were significantly higher in the p53 knockdown mice than in control mice.;As a whole this work describes the role of p53 in the induction of influenza-induced apoptosis, and how this event regulates viral replication. We also demonstrate a new function of NS1 to antagonize the antiviral response through p53 inhibition. Our work highlights the importance of p53 during the suppression and clearance of viral infection, and associated disease-related pathogenesis.