**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** LISTERIA MONOCYTOGENES(LISTERIA) IS AN INVASIVE PATHOGEN IN BOTH HUMANS AND DAIRY CATTLE. ALTHOUGH ACQUIRED ORALLY THROUGH CONTAMINATED FOOD OR FEED,LISTERIACAN BREACH THE GUT BARRIER TO INFECT MULTIPLE ORGANS. THEREFORE,LISTERIAINFECTIONCAN CAUSE ABORTION AND HAS HIGH MORTALITY RATES.THE GUT PHASE OFLISTERIAINFECTION PRECEDES SYSTEMIC SPREAD TO OTHER ORGANS, AND IS A DETERMINANT OF INFECTION OUTCOMES. INTERESTINGLY, MANY ADULT CATTLE ALSO CARRY LISTERIA WITHOUT CLINICAL SYMPTOMS, INDICATING A BALANCED STATE BETWEENLISTERIAAND THE INFECTED CATTLE. THUS, IT IS CRITICAL TO UNDERSTAND HOWLISTERIACOLONIZES CATTLE GUT TO PREVENT THE PROGRESSION TO CLINICAL INFECTION, AND TO REDUCE SHEDDING BY ASYMPTOMATIC ANIMALS. HOWEVER, SUCH KNOWLEDGE IS CURRENTLY EXTREMELY LIMITED, AND FURTHER HAMPERED BY THE LACK OF A SUITABLE BOVINE INFECTION MODEL.HERE, WE WILL PERFORM EXPERIMENTAL INFECTION STUDIES IN CALVES TO INVESTIGATE LISTERIA REPLICATION AND DISSEMINATION IN THE BOVINE GUT, AND IDENTIFY BOVINE IMMUNE RESPONSES TO INFECTION. OUR FINDINGS WILL PROVIDE AN ESSENTIAL FRAMEWORK FOR MECHANISTIC STUDIES OF LISTERIA INFECTION IN THE BOVINE HOST. RESULTS WILL ALSO FACILITATE PREDICTIVE STUDIES OF LISTERIOSIS OUTCOMES AND INTERVENTION STRATEGIES THAT MINIMIZE LETHAL SYSTEMIC INFECTION, REDUCE ANTIBIOTIC USE, AND PROMOTE ANIMAL RESISTANCE TO INFECTIOUS DISEASES. OVERALL, THIS PROJECT WILL SERVE TO PROMOTE ANIMAL HEALTH AND REDUCE ECONOMIC LOSS FOR DAIRY FARMERS.