Systems Approach for Analyzing Interactions Between Antibiotic Resistant Campylobacter jejuni, the Intestinal Microbiome and Host Immunity

Our long term goal is to develop effective inhibitors to decrease viability and fitness of C. jejuni in humans and its natural hosts to prevent disease and transmission. Our overarching hypothesis is that particular C. jejuni strains, microbial communities, and host innate and adaptive immune responses as well as suites of antibiotic resistant elements in the pathogen and microbial community interact to determine disease outcomes. Our short term goal is to examine these interactions by applying a systems-based approach to discover mechanisms of pathogenesis in AR C. jejuni in animal models of tolerance, enteric disease, and acute disease that elicits autoimmunity. Bioinformatics and core support will serve as a major discovery platform for the entire project. Mathematical models will be explored to identify key genes, transcriptional networks, and metabolic mediators of the pathogen, host and microbial communities that define these interactions, which may serve as novel drug targets. Our approaches will uncover new knowledge regarding AR C. jejuni and will serve as a guide for other investigators studying AR pathogens and their hosts.Based on extensive preliminary data for each of our long term goals, the team will carry out the following Specific Aims:(Specific Aim 1). Determine the synergistic role of host response, microbiome and antibiotic treatment in enhancing colonization, enteritis and risk of Guillain Barré syndrome after infection with C. jejuni. We will study animal models to determine the interaction pathways between the host response, microbiome and antibiotic treatment in enhancing colonization, enteritis and risk of Guillain Barré syndrome after infection with C. jejuni. Our long term goal is to develop effective inhibitors to decrease viability and fitness of C. jejuni in humans and its natural hosts to prevent disease and transmission. Our overarching hypothesis is that particular C. jejuni strains, microbial communities, and host innate and adaptive immune responses as well as suites of antibiotic resistant elements in the pathogen and microbial community interact to determine disease outcomes. Our short term goal is to examine these interactions by applying a systems-based approach to discover mechanisms of pathogenesis in AR C. jejuni in animal models of tolerance, enteric disease, and acute disease that elicits autoimmunity. Bioinformatics and core support will serve as a major discovery platform for the entire project. Mathematical models will be explored to identify key genes, transcriptional networks, and metabolic mediators of the pathogen, host and microbial communities that define these interactions, which may serve as novel drug targets. Our approaches will uncover new knowledge regarding AR C. jejuni and will serve as a guide for other investigators studying AR pathogens and their hosts. Based on extensive preliminary data for each of our long term goals, the team will carry out the following Specific Aims: (Specific Aim 1). Determine the synergistic role of host response, microbiome and antibiotic treatment in enhancing colonization, enteritis and risk of Guillain Barré syndrome after infection with C. jejuni. We will study animal models to determine the interaction pathways between the host response, microbiome and antibiotic treatment in enhancing colonization, enteritis and risk of Guillain Barré syndrome after infection with C. jejuni.