STAT2-mediated regulation of Macrophage Phenotype during Influenza and Bacterial Super-infection

Abstract

Abstract Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bacterial infection is a major complication during influenza infection that causes significant morbidity and mortality. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection in mice. Here, we investigated the role of the signaling mediator, STAT2, downstream of type I IFN signaling in both influenza infection and bacterial super-infection. Influenza-infected STAT2−/− mice had increased weight loss, increased viral burden, and increased inflammatory responses when compared to influenza-infected WT mice. Despite an exaggerated inflammatory response to influenza infection alone, influenza and methicillin resistant S. aureus (MRSA) super-infected STAT2−/− mice had lower bacterial burden, morbidity, and mortality than WT mice. STAT2−/− mice had an increased expression of markers associated with M1 (classical) and M2 (alternative) macrophages in lung during influenza or influenza-bacterial super infection compared to WT mice. Next, we found neutralization of IFNγ or Arginase1 decreased bacterial clearance in STAT2−/− mice in influenza-bacterial super-infection, suggesting that both M1 and M2 phenotype mediate host defense during influenza-bacterial super-infection. These data demonstrate a clear role for type I IFN induced STAT2 signaling in suppression of macrophage function during influenza, MRSA super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.