Contribution of type III Interferons to the pathogenesis of Staphylococcus aureus

About This Grant

SUMMARY Staphylococcus aureus is a major human pathogen that is a common cause of hospital and community acquired pneumonia, both of which lead to significant morbidity and mortality. Increasing antibiotic resistance and prevalence of methicillin resistant strains is of critical concern. The long-term goal of our research is to better understand the host-pathogen interaction between S. aureus and the host innate immune system. It is hoped that an improved understanding of this interaction could lead to novel therapies targeting the bacterium or modulating the host to thwart this multidrug resistant pathogen. The objective of this proposal is to understand how type III IFN contributes to the pathogenesis of S. aureus infection. The rationale for this approach is that new targets are needed to either develop antibiotics/inhibitors or vaccines against S. aureus. Studies investigating type III IFN to-date are largely focused on viral infections where activation of signaling is important to control the infection. We have shown that type III IFN signaling contributes to the pathogenesis of acute S. aureus pneumonia. We have demonstrated alterations to the alveolar macrophage population can improve bacterial clearance by manipulating the pathways identified from our RNA-seq analysis. Investigation of both differential transcripts and proteins indicates changes to the epithelial barrier occur when type III IFN signaling is present. We also have data that shows that S. aureus strains can activate type I and III IFN signaling with variable intensity and independent of each pathway. Precise mechanisms for this involvement of type III IFN signaling are still lacking. This contribution is significant as it will provide a deeper understanding on how the type III IFN pathway influences the clearance of S. aureus from the airway. Completion of our objectives will be accomplished by pursuing two specific aims: 1) Determining the role of type III IFN in pathogenesis through studies on MID1 in alveolar macrophages, the role of IL-1β in immunopathology its effect in the airway barrier and 2) defining how S. aureus activates type III IFN, its comparison to type I IFN signaling and the utility in targeting this pathway. The innovation of this research is both conceptual and technical. The concept that the pathway is inhibitory to bacterial clearance through the epithelial response to type III IFN signaling is unique. We will examine both direct effects on airway epithelial cells as well as the effects IFN signaling has on professional phagocytes. It is also thought activation of type I&III IFN is linked, and we provide evidence this is not entirely the case. We will utilize techniques across multiple fields, microbiology, immunology, cell and molecular biology, utilizing a well-tested animal model of pneumonia, in vitro functional and primary cell culture assays and global approaches to understand the host response such as RNA-seq. At the conclusion of these studies, we will have expanded our knowledge on how an innate signaling pathway can impact negatively on acute bacterial infection in the airway, how this pathway can be activated and how it can coordinate multiple cells in response to its activation.