NON-TYPHOIDAL SALMONELLAE ARE THE LEADING CAUSE OF BACTERIAL FOODBORNE GASTROENTERITIS AND BOVINE FOOD PRODUCTS ARE FREQUENTLY IMPLICATED IN DISEASE OUTBREAKS. THE DAUNTING RATE OF SALMONELLA INFECTIONS IN HUMANS COMBINED WITH THE INCREASING NUMBER OF MULTIPLE DRUG RESISTANT (MDR) ISOLATES IS AN ALARMING PUBLIC HEALTH THREAT. MDR SALMONELLA INFECTIONS ARE FREQUENTLY TRACED TO BOVINE SOURCES, MAKING IT IMPERATIVE TO DESIGN NOVEL, NON-ANTIMICROBIAL STRATEGIES TO ELIMINATE MDR SALMONELLA FROM CATTLE. IN THIS BASIC SCIENCE PROPOSAL, WE WILL ESTABLISH THE ROLE OF A HOST-CELL PROTEIN, MARCKS (MYRISTOYLATED ALANINE-RICH C-KINASE SUBSTRATE), IN SALMONELLA INFECTIONS. WE HYPOTHESIZE THAT MARCKS PROTEIN FUNCTION IS ESSENTIAL FOR SALMONELLA-INDUCED NEUTROPHIL RECRUITMENT AND ACTIVATION, EPITHELIAL INVASION, AND THE OVERALL SURVIVAL OF SALMONELLA IN THE HOST INTESTINE. USING A SPECIFIC INHIBITOR OF MARCKS FUNCTION, WE WILL ESTABLISH THE ROLE OF MARCKS IN IMMUNE SIGNALING AND SALMONELLA COLONIZATION OF THE CALF GUT. THESE EXPERIMENTS WILL (1) ESTABLISH THE BASIC BIOLOGY OF MARCKS PROTEIN DURING INFECTION AND (2) ESTABLISH WHETHER A MARCKS PEPTIDE INHIBITOR IS A VIABLE HOST-DIRECTED THERAPEUTIC TO TREAT BOVINE SALMONELLOSIS. SALMONELLA INFECTIONS ARE A THREAT TO BOTH HUMAN AND BOVINE HEALTH SO ALTERNATIVES TO TRADITIONAL ANTIMICROBIALS ARE CRITICALLY NEEDED TO COMBAT THIS IMPORTANT PATHOGEN. THE PROPOSED STUDIES WILL DIRECTLY INFORM DEVELOPMENT OF A NON-ANTIMICROBIAL THERAPEUTIC TO PREVENT AND TREAT SALMONELLA IN CATTLE.