Influenza A virus-induced autophagy contributes to enhancement of virus infectivity by SOD1 downregulation in alveolar epithelial cells.

Infection with influenza A virus (IAV) A/WSN/1933 (H1N1) causes oxidative stress and severe lung injury. We have demonstrated that the generation of reactive oxygen species (ROS) during IAV infection is tightly regulated by superoxide dismutase 1 (SOD1) and correlated with viral replication in alveolar epithelial cells. However, the molecular mechanism underlying SOD1 reduction during IAV infection is uncertain. Here we demonstrate that the autophagy pathway is activated by IAV infection and involved in enhanced ROS generation in the early phase of infection. We observed that IAV infection induced autophagic vacuolation, leading to autophagic degradation of cellular proteins, including the protease sensitive antioxidant SOD1. Silencing of the microtubule-associated protein 1A/1B-light chain 3 (LC3) gene in A549 cells supported the critical role of autophagy in the ROS increase. The decrease in viral titer and viral polymerase activity caused by LC3 silencing or the autophagy inhibitor clearly evidenced the involvement of autophagy in the control of ROS generation and viral infectivity. Therefore, we concluded that early stage IAV infection induces autophagic degradation of antioxidant enzyme SOD1, thereby contributing to increased ROS generation and viral infectivity in alveolar epithelial cells.