IFN/SOCS1 signaling during post-influenza bacterial infection

Influenza and influenza-complicated pneumonia cause up to 50,000 deaths annually in the United States despite the availability of vaccines and antiviral drugs. Although influenza A virus (IAV) infection alone can cause pneumonia, secondary infection by Streptococcus pneumoniae leads to excess morbidity and mortality. IAV infection induces peak type I IFN (IFN-I, i.e., IFNa/ß) and IFN-? production at the innate and adaptive phase of infection, respectively. IFN-I signaling promotes monocyte recruitment but inhibits neutrophil recruitment after IAV infection. Accordingly, IFN-I has been shown to suppress neutrophil-mediated bacterial control. Supporting data in this application show that IFN-I plays a dual role in IAV/S. pneumoniae coinfection by inhibiting initial bacterial killing while also preventing a detrimental IFN-? response. Suppressor Of Cytokine Signaling 1 (SOCS1) is a feedback inhibitor of the IFN/STAT1 signaling pathway. Novel data indicate that SOCS1 exacerbates antibacterial complications during acute IAV infection and prolongs host susceptibility to invasive S. pneumoniae infection after viral clearance. However, the mechanism by which SOCS1 promotes IAV/S. pneumoniae co- pathogenesis remains to be established. Resident alveolar macrophages are essential and normally sufficient for clearance of a physiologically relevant dose of S. pneumoniae. As airway sentinel cells, alveolar macrophages also produce acute inflammatory cytokines to recruit neutrophils for additional bacterial killing. However, these antibacterial functions of alveolar macrophages, including phagocytosis and innate signaling, are suppressed after IAV infection. Monocytes recruited during acute IAV infection increase lung damage and promote host susceptibility to pneumococcal pneumonia. Conversely, after viral clearance, these CCR2-recruited monocytes can differentiate into alveolar macrophages to confer antibacterial protection. It remains unclear how this alveolar macrophage replenishment mechanism is orchestrated during resolution of IAV infection, but novel data in the application suggest that SOCS1 inhibits alveolar macrophage restoration after viral clearance. Thus, the central hypothesis of this application is that IFN/SOCS1 signaling in IAV infection inhibits alveolar macrophage-dependent antibacterial protection, thereby predisposing the host to secondary pneumococcal pneumonia. This hypothesis will be tested in three specific aims: 1) define how differential effector cells contribute to the paradoxical role of IFN-I, 2) determine how SOCS1 contributes to the synergistic suppression of antibacterial immunity by IFN-I and IFN-?, and 3) establish how SOCS1 regulates monocyte differentiation and alveolar macrophage restoration after viral clearance. Given that IFN/SOCS1 signaling is a characteristic feature of acute viral infection, identifying how this axis renders hosts unable to control opportunistic bacteria will provide novel understanding of immune complications associated with invasive bacterial pneumonia.