Influenza-Induced Oxidative Stress Sensitizes Lung Cells to Bacterial-Toxin-Mediated Necroptosis

Pneumonias caused by influenza A virus (IAV) co- and secondary bacterial infections are characterized by their severity and high mortality rate. Previously, we have shown that bacterial pore-forming toxin (PFT)-mediated necroptosis is a key driver of acute lung injury during bacterial pneumonia. Here, we evaluate the impact of IAV on PFT-induced acute lung injury during co- and secondary Streptococcus pneumoniae (Spn) infection. We observe that IAV synergistically sensitizes lung epithelial cells for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacoelogical induction of oxidative stress without virus sensitizes cells for PFT-mediated necroptosis. Antioxidant treatment or inhibition of necroptosis reduces disease severity during secondary bacterial infection. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identify necroptosis inhibition and antioxidant therapy as potential intervention strategies. [Display omitted] •IAV synergistically sensitizes pulmonary cells for PFT-mediated necroptosis•Oxidative stress induced by IAV promotes PFT-mediated necroptosis•Oxidative stress without virus sensitizes cells for PFT-mediated necroptosis•Antioxidant treatment or necroptosis inhibition reduces disease severity during SBI Gonzalez-Juarbe et al. identify necroptosis as a pathway modulating disease severity during secondary bacterial infection (SBI) following influenza virus infection. They show that influenza-virus-induced oxidative stress is required to sensitize pulmonary cells to the pro-necroptotic activity of bacterial pore-forming toxins, providing a mechanism to explain the necrosis observed during SBI.