Regulation of mucosal immune responses upon polymicrobial exposure to viral and bacterial pathogens in the lung

A significant portion of influenza-associated morbidity and mortality has been primarily attributed to secondary bacterial pneumonia caused by S. aureus. However, to date, the underlying mechanisms of these polymicrobial diseases are poorly defined. The research documented in this thesis investigated the mucosal immune responses and disease outcome upon polymicrobial exposure to influenza and S. aureus. Upon establishing a murine model of a single exposure to S. aureus in the lung, we found a marked increased in NK cells, but not other lymphocytes in the airway. This enhanced recruitment of NK cells correlated with high levels of IL-15 production by AMs. By using NK cell depleted and IL-15 KO mice, we were able to demonstrate that these mice were susceptible to staphylococcal infection in spite of the increased in neutrophils and AMs in the lung. These findings showed a novel and critical role of NK cells in host defense against pulmonary S. aureus infection. We next examined whether a prior influenza infection would impact anti-staph host responses in the lung. We found that exposing mice to a prior influenza infection weakened anti-staph NK cell responses in the lung and made these mice more susceptible to S. aureus pneumonia. Interestingly, we found that host defense could be restored in flu-infected mice that obtained adoptively transferred naive NK cells. Our findings suggest that NK cells but not other innate cells are required for the clearance of S. aureus. Having shown that exposure to bacteria typically occurs after the initiation of anti-viral immune response, we further explored whether influenza adaptive immunity also could be modified to a subsequent S. aureus superinfection. We showed that exposure to S. aureus bacterial superinfection during a primary influenza infection caused a decrease in the CD8+T cell responses. In spite of these findings, exposing mice to S. aureus during acute influenza infection had no significant effect on effector CD8+T cells or antibody responses upon secondary viral challenge. Collectively, our findings provide novel insights that allow better understanding of polymicrobial diseases and will further assist in the future development of vaccines and treatment options necessary to combat the many influenza pandemics to come.