Interferons in Influenza A Virus and Streptococcus Pneumoniae Co-Pathogenesis

Secondary pneumococcal pneumonia postinfluenza significantly increases the disease burden associated with influenza A virus (IAV) infection. IAV induced interferons (IFN) play a crucial role in antiviral immunity. However, recent reports have indicated that influenza-induced IFN-I and IFN- γ signaling suppress innate antibacterial immunity by distinct mechanisms, thereby increasing host susceptibility to secondary bacterial pneumonia. Despite their detrimental role, the interplay between them remains poorly understood. In this dissertation, we have investigated the relative importance of IFN-I and IFN-γ pathways in the pathogenesis of IAV/ Streptococcus Pneumoniae (SPn) coinfection. Using gene knock-out models and neutralizing in vivo antibodies, we demonstrated that IFN-I and IFN-γ inhibit acute bacterial clearance post-IAV infection. However, IFN-γ plays a more critical role. Additionally, we found that IFN-I signaling is essential for preventing IFN-γ hyperproduction and animal death during coinfection, indicating the dual role of IFN-I, which was novel. Moreover, we show that both IFN-I and IFN-γ employ distinct mechanisms to regulate inflammatory cytokine response and immune cell recruitment during copathogenesis. Given the dominant role of IFN-γ in the progression of coinfection, we further investigated the effect of immune predisposition on susceptibility to coinfection. To that end, we demonstrated that pathogenicity to coinfection remains distinct between BALB/c and C57BL/6 (B6) mice that recapitulate Th2- and Th1-biased responses, respectively. Prior infection with a low-virulent IAV strain (X31) renders B6 mice extremely susceptible to superinfection compared to the resistant BALB/c mice. We found that neither the viral nor the bacterial infection alone induced IFN-γ response in both strains of mice. However, the coinfection resulted in a robust IFN-γ response in the B6 mice, not the BALB/c mice. Furthermore, this IFN-γ response in the B6 mice inhibited neutrophil recruitment and innate bacterial clearance. Additionally, we also demonstrated that neutrophils in BALB/c mice are required for effective bacterial control. Collectively, our results indicate that Th1-biased immune predisposition plays an important role in determining the outcome during IAV/ SPn coinfection. Altogether, our work has demonstrated the relative importance and the regulation between IFN-I and IFN-γ during the coinfection pathogenesis, which is imperative for understanding the complex pathogenic mechanisms.