The Role of Inhibitory Mechanisms and Memory in Influenza Associated Bacterial Super-Infections.

Influenza associated secondary bacterial super-infections have devastating impacts on health and result in an increased risk of morbidity and mortality. The current field suggests that immunological mechanisms directed against primary influenza infection act to suppress anti-bacterial mechanisms resulting in a beneficial lung environment for colonization by opportunistic pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). Understanding these aberrant immune mechanisms can provide insight into immunological pathways which can be targeted for prevention of bacterial super-infections. With this in mind I investigated the role that immune inhibitory-receptors play in bacterial super-infection. Previous studies on chronic and acute viral infections suggested that programmed death-1 (PD-1), a well-known inhibitory receptor, may play a role in weakening the adaptive immune response, in particular the T cell response, to viral infection by suppressing proliferation and production of key cytokines related to viral clearance. To study PD-1, I performed mouse studies using wild type (WT) and PD-1 global knock-out mice infected with influenza followed by a secondary bacterial infection with MRSA. I also performed antibody blockade studies in WT mice targeting PD-1 and its ligand Pd-l1. We observed a change in expression of other inhibitory markers, suggesting that they may work in conjunction with each other and the loss of one may alter the expression of the others. In conjunction with the PD-1 studies, I also developed a project looking at the role of immune memory in susceptibility to secondary infections. I found that immune memory to heterotypic influenza strains resulted in a significant decrease in MRSA colonization. Following this observation, I studied multiple pathways commonly associated with bacterial super-infections. Results from these studies highlighted changes in both the innate and adaptive immune systems suggesting a more effective viral response leading to less hindrance of the innate immune system and a more effective anti-bacterial response. These studies presented herein highlight two novel areas in the field of super-infection. The first being the role that inhibitory pathways play in secondary infections, and the second being the importance of understanding how pre-existing immunity to pathogens can shape our immune response to secondary infections