Interbacterial AI-2 signaling orchestrates chemotaxis, attachment, and antimicrobial peptide resistance to promote Salmonella colonization

Quorum sensing enables bacteria to coordinate collective behaviors crucial for survival and infection. Here, we show that Salmonella Typhimurium employs LuxS/autoinducer-2 (AI-2) signaling to regulate multiple stages of pathogenesis. AI-2 functions as a chemoattractant and modulates the expression of chemotaxis and motility-associated genes, promoting flagellar assembly and adhesion to the epithelial host cells. Loss of LuxS/AI-2 signaling diminishes hilD and SPI-1 gene expression, unveiling a regulatory link between quorum sensing and virulence determinants. Further, AI-2 signaling governs resistance to antimicrobial peptides through the pmrD/AB system and supports intracellular proliferation in the host cells. Transcriptomic profiling revealed that LuxS/AI-2 controls distinct gene networks spanning invasion, survival, and immune evasion. In murine infection models, inhibition of LuxS/AI-2 signaling in combination with antibiotics can be an alternative therapeutic approach. Our findings establish LuxS/AI-2 as an integrated regulatory hub in Salmonella pathogenesis and highlight quorum sensing as a targetable mechanism for therapeutic intervention.