Regulation of IFN-γ by IL-13 dictates the susceptibility to secondary post-influenza MRSA pneumonia (INM3P.439)

Abstract Post-IAV superinfections are the primary cause of deaths during IAV pandemics. The superinfection in mice 7 days after IAV infection results in exacerbated bacterial pneumonia mediated by type I and II IFNs. However, the sequelae of cytokine responses early in IAV infection, that eventually determines the later susceptibility is not understood. Here we examined whether the susceptibility to superinfection with MRSA varies during IAV infection. In the first 3 days of IAV infection mice had increased resistance to MRSA superinfection, which required IFNAR and IL-13 signaling to inhibit IFN-γ. IFN-γ-mediated high susceptibility to MRSA pneumonia 7 days after IAV infection was associated with increased IL-13Rα2 production, and was reversible by treatment with mrIL-13 or anti-IL-13Rα2. Thus, early in IAV infection IFNAR signaling maintained IL-13, which increased resistance to MRSA. Then, as IAV infection progressed, the capacity for IL-13 signaling was inhibited, in part by increased IL-13Rα2, resulting in increased IFN-γ levels and susceptibility to MRSA superinfection. Thus, IAV induces a sequence of cytokine responses where early IFNAR-dependent IL-13 signaling suppresses IFN-γ production resulting in enhanced resistance to MRSA challenge. Understanding these cytokine sequelae is critical to development of immunotherapies for IAV-MRSA coinfection since perturbations in the sequence of these events at the wrong time could increase susceptibility to MRSA and/or IAV.