Our objectives target three factors that influence Salmonella colonization, pathogenesis, and persistence. These factors include virulence mechanisms of Salmonella, the tactical response from the host, and interactions with the microbiota residing within the host. Our systematic approach integrates these research areas into three complementary objectives: Objective 1: Investigate the impact of antibiotic usage on influencing Salmonella virulence mechanisms and enhancing antibiotic resistance. Objective 2: Develop novel non-antibiotic intervention strategies such as beneficial microbes and vaccines to limit Salmonella colonization, persistence and shedding. Objective 3: Evaluate immune networks and identify porcine genes for their relationship with the host microbiota to reduce Salmonella colonization, persistence, and shedding.