Mechanisms conferring multi-layered protection against intestinal Salmonella Typhimurium infection

Enteropathogens cause many gastrointestinal infections every year. However, it is often overlooked that many individuals remain asymptomatic despite exposure to these pathogens. The mechanisms underlying this effective protection against infection may hold important clues for disease prevention or therapy. Here, we focus on Salmonella enterica serovar Typhimurium (S. Tm), a well-studied enteropathogen closely related to commensal Escherichia coli. We discuss the host's multi-layered defence mechanisms that protect against S. Tm infection of the intestine, with an emphasis on the microbiota, epithelial barrier, and immune system. Perturbations in these defences, such as microbiota dysbiosis, variability in epithelial barrier integrity, or immune defects, can impair protection and increase susceptibility to disease. Additionally, we review the virulence mechanisms and metabolic adaptations that S. Tm has evolved to overcome these protective layers. This complex interplay between host defence layers and pathogen traits, shaped by both intrinsic and extrinsic factors, ultimately determines whether exposure results in asymptomatic carriage or symptomatic disease. Understanding these dynamics is critical for developing targeted interventions to prevent S. Tm infections and mitigate their impact on public health.