** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** SUMMARY:SALMONELLA INFECTIONS ARE OF SIGNIFICANT CONCERN FOR BOTH ANIMAL AND HUMAN HEALTH. IN CATTLE, SALMONELLA INFECTIONS CAN CAUSE SALMONELLOSIS, WHICH IS CHARACTERIZED BY FEVER, DIARRHEA, AND RAPID DEHYDRATION, LEADING TO STEEP DROPS IN MILK PRODUCTION, REDUCED FEED EFFICIENCY, ABORTIONS, AND EVEN DEATH. WITH ANTIMICROBIAL RESISTANCE ON THE RISE AND THE EMERGENCE OF MULTI-DRUG RESISTANT SALMONELLA, THE DEVELOPMENT OF NOVEL STRATEGIES TO COMBAT SALMONELLA INFECTION IS A HIGH PRIORITY. IN POULTRY, THE NOVEL STRATEGY OF PRE-COLONIZING THE GUT WITH NON-VIRULENT SALMONELLA STRAINS IS ALREADY BEING COMMERCIALLY IMPLEMENTED TO COMBAT ENTERIC DISEASE. THIS IS BELIEVED TO OCCUR THROUGH THE PROCESS OF COMPETITIVE EXCLUSION, AN ECOLOGICAL PRINCIPLE THAT STATES IF AN ORGANISM IS OCCUPYING A NICHE, IT CAN PREVENT OTHER CLOSELY RELATED ORGANISMS FROM OCCUPYING THAT SAME NICHE. I HYPOTHESIZE THAT THE SAME STRATEGY CAN BE UTILIZED IN A BOVINE MODEL BY PRE-COLONIZING CALVES WITH SALMONELLA ENTERICA SEROVAR CERRO (SC) TO REDUCE THE IMPACT OF SALMONELLOSIS. WE HAVE DOCUMENTED CALVES NATURALLY BEING COLONIZED WITH SC AT EMMONS BLAINE DAIRY AT THE UW-MADISON ARLINGTON AGRICULTURAL RESEARCH STATION AND HAVE RECORDED CASES OF SC BEING ISOLATED FROM THE FARM AS FAR BACK AS 2016. TO ASSESS THE PROTECTIVE POTENTIAL OF SC, I WILL FIRST DOCUMENT THE PERSISTENCE AND GENOMIC STABILITY OF SC AT THE FARM BY PERFORMING WHOLE GENOME SEQUENCING. LASTLY, I PROPOSE THE USE OF A SIMPLIFIED IN VITRO COMPETITION ASSAY TO ASSESS THE ABILITY OF SC TO OUTCOMPETE OTHER SEROVARS OF SALMONELLA THAT ARE KNOWN TO CAUSE DISEASE.IMPORTANCE:THE EMERGENCE OF MULTI-DRUG RESISTANT PATHOGENS IS OF GREAT CONCERN IN THE UNITED STATES. DECADES OF ANTIMICROBIAL USE IN THE ANIMAL FOOD AND HEALTH INDUSTRY HAS RESULTED IN INCREASES IN ANTIMICROBIAL RESISTANCE. WITH SALMONELLA BEING A ZOONOTIC PATHOGEN, BOTH THE HEALTH OF ANIMALS AND HUMANS ARE AT RISK WHEN SALMONELLA DEVELOP MULTIPLE RESISTANCE TO ANTIBIOTICS. WHILE VACCINES AGAINST SALMONELLA INFECTIONS EXIST, THEY ARE EITHER NARROWLY SPECIFIC TO A SINGLE SEROTYPE OR HAVE PROVEN TO BE EQUIVOCAL IN THEIR EFFECTIVENESS. THROUGH UTILIZATION OF THE COMPETITIVE EXCLUSION PRINCIPLE AND THE USE OF PRE-COLONIZATION OF CATTLE WITH SC, IT IS OUR HOPE TO USE THIS NOVEL APPROACH TO REDUCE THE IMPACT OF SALMONELLOSIS SUCH THAT VACCINE USE AND ANTIMICROBIAL USE CAN BE REDUCED, AN IMPORTANT STEP TOWARD MITIGATING THE GLOBAL EPIDEMIC OF ANTIMICROBIAL RESISTANCE.