Project Summary/Abstract T-helper (Th)-17 lymphocytes are central mediators of adaptive type 17 immunity, which is characterized by the expression of IL-17 isoforms including IL-17A. Decreased type-17 signaling increases severity of infections in humans and mice, but aberrant type 17 inflammation is implicated in autoimmune diseases. Effective host defense thus requires type-17 immune calibration, but mechanisms are poorly understood. A gut-lung axis has been proposed to coordinate homeostatic protection and acute host defense against infection. However, a better mechanistic understanding of this concept is needed to better understand links between the gut-lung axis and host defense. Factors that alter the gut microbiome are heterogeneous, but common settings include diet, digestive disease states such as acute infections or colitis, and transient changes due to medical treatments such as antibiotics. These changes have been studied most extensively in the context of chronic diseases such as rheumatologic disease, asthma, cystic fibrosis, COPD, and HIV. However, in homeostatic and acute infection settings, effects of the microbiome on immune defense are poorly understood. There is evidence in the literature suggesting that changes in the gut microbiome following antibiotic administration alter immune system responses to subsequent infections, including pneumonia. Prior studies have also shown that antibiotics reduce expression of IL-17-mediated host defense signals across distant organs. Since gut microbial homeostasis influences Th17 cell numbers both locally in the intestine and remotely in other tissues, I will explore how increases in sensitivity to infection are driven by the gut-lung axis. I postulate that a gut-lung axis promotes host defense through mucus barriers, the gut microbiome, and regulation of Th17 immunity. Here I propose to examine the function of the gut-lung axis mechanistically by focusing on how the gut microbiome affects Th17 lymphocyte populations in the lungs. I hypothesize that the gut microbiome promotes respiratory host defense through epithelium-derived signals that establish type 17 immune tone. I will test this in two Specific Aims that evaluate homeostatic defense (Aim 1) and acute responses to inflammation and bacterial pneumonia (Aim 2). My studies will reveal novel links between epithelial function and the establishment of Th17 immunity. There are strong correlations between the gut microbiome and immune responses in the lungs in settings of chronic diseases. However, gut-lung axis regulation of anti- bacterial defense in acute infections is poorly understood.