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

Pneumonia 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 toxins (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. IAV synergistically sensitized lung epithelial cells for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacological induction of oxidative stress sans virus sensitized cells for PFT-mediated necroptosis. Inhibition of MLKL, the effector of necroptosis reduced disease severity during secondary bacterial infection. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identifies necroptosis inhibition and antioxidant therapy as potential intervention strategies.