NOX2 OXIDASE AS A THERAPEUTIC TARGET IN INFLUENZA A VIRUS‐INDUCED LUNG INJURY

Continuing threats of new pandemic strains of influenza A virus highlight an urgent need for novel pharmacological strategies that reduce viral replication and the lung pathology, irrespective of the infecting strain. The pathology to pandemic influenza consists of a persistent infiltration of inflammatory cells into the airways leading to excessive reactive oxygen species (ROS) production. We investigated the primary source of inflammatory cell ROS, Nox2 oxidase, as a pharmacological target against influenza A viruses of varying virulence. Wild‐type (C57BL/6) and Nox2−/− mice were infected with influenza A virus of mild (H3N2; 104 PFU/mouse) or high (H1N1; 50 PFU/mouse) virulence. Lungs of Nox2−/− mice displayed a substantial reduction in viral titer, airways inflammation and oedema compared to WT mice. Airway macrophages, neutrophils and T cells of Nox2−/− mice produced minimal superoxide compared to controls. The magnitude of airway and spleen influenza‐specific DbNP366+ and DbPA224+ CD8+ T cells were similar in WT and Nox2−/− mice indicating that the adaptive immune response that clears virus is preserved in Nox2−/− mice. In vivo treatment with the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide following H3N2 or H1N1 infection. In conclusion, Nox2 inhibition should be considered for seasonal and pandemic control of influenza A virus.