Data from: Mucus-derived glycans are inhibitory signals for <em>Salmonella</em> Typhimurium SPI-1-mediated invasion

Mucus forms a critical barrier against enteric pathogens like Salmonella enterica serovar Typhimurium. While in vivo studies indicate that secreted, gel-forming mucins and specifically Core 3 glycosylation are protective against S. Typhimurium, the molecular mechanisms involved remain unclear. Here, we demonstrate that native intestinal mucins inhibit Salmonella invasion of colonic epithelial cells by downregulating the type 3 secretion system (T3SS) through suppression of the key virulence regulator, HilD. By measuring changes in the transcriptional profile (qPCR, RNA-seq), proteomics (DIA-based), growth, and HT-29 host cell invasion, our study identifies mucin glycans and specific mucin sugars, namely N-acetyl galactosamine (GalNAc) and N-acetyl glucosamine (GlcNAc), as the components responsible for mucin’s anti-virulence effect, likely via interaction with HilD's putative carbohydrate-binding domain. Notably, we find the native presentation of these sugars is important for activity. These insights provide a mechanistic foundation for mucin-based strategies to combat enteric infections and, given the prevalence of homologous AraC-type regulators in other pathogens, suggest mucins' potential as broad-spectrum anti-virulence agents.