Type I IFN Signaling Is Essential for Preventing IFN- gamma Hyperproduction and Subsequent Deterioration of Antibacterial Immunity during Postinfluenza Pneumococcal Infection

Postinfluenza bacterial pneumonia is a significant cause of hospitalization and death in humans. The mechanisms underlying this viral and bacterial synergy remain incompletely understood. Recent evidence indicates that influenza-induced IFNs, particularly type I IFN (IFN-I) and IFN-gamma, suppress antibacterial defenses. In this study, we have investigated the relative importance and interplay of IFN-I and IFN-gamma pathways in influenza-induced susceptibility to Streptococcus pneumoniae infection. Using gene-deficient mouse models, as well as in vivo blocking Abs, we show that both IFN-I and IFN-gamma signaling pathways contribute to the initial suppression of antibacterial immunity; however, IFN-gamma plays a dominant role in the disease deterioration, in association with increased TNF-alpha production and alveolar macrophage (AM) depletion. We have previously shown that IFN-gamma impairs AM antibacterial function and thereby acute bacterial clearance. The findings in this study indicate that IFN-gamma signaling also impairs AM viability and alpha beta T cell recruitment during the progression of influenza/S. pneumoniae coinfection. Macrophages insensitive to IFN-gamma mice express a dominant-negative mutant IFN-gamma R in mononuclear phagocytes. Interestingly, macrophages insensitive to IFN-gamma mice exhibited significantly improved recovery and survival from coinfection, despite delayed bacterial clearance. Importantly, we demonstrate that IFN-I receptor signaling is essential for preventing IFN-gamma hyperproduction and animal death during the progression of postinfluenza pneumococcal pneumonia.