**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** THE RESIDENT MICROBIOTA LINING GUT AND RESPIRATORY MUCOSAE PROVIDE CRITICAL DEFENSE AGAINST INVADING PATHOGENS AND OVERGROWTH OF RESIDENT PATHOBIONTS, A MECHANISM TERMED COLONIZATION RESISTANCE (CR). THIS MECHANISM INCORPORATES BOTH DIRECT PATHWAYS OF COMPETITIVE EXCLUSION OF PATHOGENS AND INDIRECT PATHWAYS THAT ENHANCE HOST IMMUNITY. ALTHOUGH CR IS BEST UNDERSTOOD IN THE CONTEXT OF ENTERIC INFECTION, GUT BACTERIA ARE ALSO FOUND IN HEALTHY LUNGS WHERE THEY IMPACT PULMONARY CYTOKINE LEVELS AND ALVEOLAR MACROPHAGE (AM) FUNCTION, THUS INFLUENCING THE RISK OF PNEUMONIA. THEREFORE, PULMONARY CR MAY INVOLVE BOTH INTERBACTERIAL ANTAGONISM AND INDIRECT IMMUNOMODULATION. THERE IS A CRITICAL NEED TO UNDERSTAND HOW BOVINE ENTEROPATHOGENS IMPACT CR IN THE GUT AND LUNG. MY LONG-TERM GOAL IS TO UNDERSTAND THE RELATIONSHIPS AMONG SALMONELLA SPP., THE MICROBIOTA AND HOST IMMUNITY IN RELATION TO ANIMAL HEALTH AND FOOD SAFETY. SALMONELLA ENTERICA THREATEN BOTH BOVINE AND HUMAN HEALTH. SALMONELLA DUBLIN(SED) IS A CATTLE-ADAPTED SEROTYPE THAT CAUSES SYSTEMIC INFECTIONS AND PREDOMINANTLY MANIFESTS AS PNEUMONIA IN CALVES, IN CONTRAST TO THE GENERALIST SEROTYPES THAT PRIMARILY CAUSE LOCALIZED ENTERITIS. SALMONELLA HAS EVOLVED SEVERAL MECHANISMS TO OVERCOME CR. SALMONELLA EXPLOITS THE INFLAMMATORY RESPONSE TO PROMOTE GUT COLONIZATION. IN ADDITION, TYPE VI SECRETION SYSTEMS (T6SS) INJECT TOXIC EFFECTOR PROTEINS TO KILL BACTERIA AND EUKARYOTIC CELLS. DESPITE YEARS OF STUDY, THE MECHANISMS BY WHICH SED OVERCOME CR ARE POORLY DESCRIBED. MY PRELIMINARY DATA SUGGEST THAT GUT ASSOCIATED LUNG BACTERIA (GALB) MAY IMPACT PULMONARY PATHOGEN COLONIZATION IN CALVES. I HYPOTHESIZE THAT GALB INDUCE PULMONARY IMMUNITY TO RESIST SED INFECTION AND SED USES T6SS TO OVERCOME CR IN THE GUT AND LUNG.