NOX2 oxidase inhibitor GSK2795039 possess antiviral activity against H1N1 influenza A virus in vitro and vivo

The continuous zoonotic circulation and reassortment potential of influenza A viruses (IAV) in nature represents an enormous public health threat to humans. Beside vaccination antivirals are needed to efficiently control spreading of the disease. The previous research has shown that NOX2 involved in IAV replication, but the detailed mechanism has not been reported. In the present study we investigated the roles of NOX2 in host in-flammatory response and IAV replication using a novel inhibitor GSK2795039. The drug significantly reduced H1N1 virus induced NOX2 activity and ROS release in human lung epithelial cells. The results of time course experiments suggested that GSK2795039 inhibited an early post-entry step of viral infection. Concomitantly, there was a decreased expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-beta and interleukin (IL)-6) in NOX2 suppressed cells. In vivo, compared with control groups, suppression of NOX2 improved the survival rate of mice infected with H1N1 virus (42.9% in GSK2795039 treated mice versus >0% of control mice) and viral burden also decreased in the GSK2795039 treated group. Thus, our data demonstrated a critical role for NOX2 in the establishment of H1N1 infection and subsequent inflammatory reactions, which suggest that GSK2795039 may be a potential therapeutic drug for IAV infection.

Automated summary

By using a novel inhibitor GSK2795039, we investigated the roles of NOX2 in host inflammatory response and IAV replication. The drug significantly reduced H1N1 virus induced NOX2 activity and ROS release, as well as decreased the expression of pro-inflammatory cytokines. In vivo experiments showed that suppression of NOX2 improved the survival rate of mice infected with H1N1 virus and reduced viral burden. Our data demonstrated a critical role for NOX2 in the establishment of H1N1 infection and subsequent inflammatory reactions, suggesting that GSK2795039 may be a potential therapeutic drug for IAV infection.