Regulation of IFN-γ by IL-13 dictates susceptibility to secondary postinfluenza MRSA pneumonia.

Superinfection in mice at day 7 postinfluenza infection exacerbates bacterial pneumonia at least in part via downstream effects of increased IFN-γ signaling. Here we show that up to 3 days postinfluenza infection, mice have reduced susceptibility to superinfection with methicillin-resistant Staphylococcus aureus (MRSA), but that superinfection during that time exacerbated influenza disease. This was due to IL-13 signaling that was advantageous for resolving MRSA infection via inhibition of IFN-γ, but was detrimental to the clearance of influenza virus. However, if superinfection did not occur until the near resolution of influenza infection (day 7), IL-13 signaling was inhibited, at least in part by upregulation of IL-13 decoy receptor (IL-13Rα2), which in turn caused increases in IFN-γ signaling and exacerbation of bacterial infection. Understanding these cytokine sequelae is critical to development of immunotherapies for influenza-MRSA coinfection since perturbations of these sequelae at the wrong time could increase susceptibility to MRSA and/or influenza.