Mucus-derived glycans are inhibitory signals for Salmonella 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 through suppression of the key virulence regulator, HilD. Our study identifies mucin glycans and specific mucin sugars, namely N-acetyl galactosamine and N-acetyl glucosamine, as the components responsible for mucin's anti-virulence effect, likely via functional or direct interaction with HilD's putative carbohydrate-binding domain. Notably, we find that 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.
Authors
- Michaela A. Gold (ORCID: https://orcid.org/0000-0002-0605-1971)
- Kelsey M. Wheeler (ORCID: https://orcid.org/0000-0001-5947-5025)
- Jeongmin Song (ORCID: https://orcid.org/0000-0002-6777-3505)
- Corey A. Stevens (ORCID: https://orcid.org/0000-0002-9619-7869)
- Jessica R. Kramer (ORCID: https://orcid.org/0000-0002-4268-0126)
- Marcus Fulde (ORCID: https://orcid.org/0000-0003-0469-3951)
- Amanda M. Wood (ORCID: https://orcid.org/0009-0009-8648-2437)
- Katharina Ribbeck (ORCID: https://orcid.org/0000-0001-8260-338X)
- Bradley S. Turner (ORCID: https://orcid.org/0000-0001-8086-2118)
- Karsten Tedin (ORCID: https://orcid.org/0000-0003-2109-0730)
- Deniz Uzun
- Gerardo Cárcamo-Oyarce (ORCID: https://orcid.org/0009-0004-4827-4892)
Institutions
- Cornell University (US)
- University of Utah (US)
- Massachusetts Institute of Technology (US)
- Freie Universität Berlin (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1016/j.celrep.2025.116304
- Citations
- 3
- Primary Topic
- Bacteriophages and microbial interactions
- Type
- article
- Field-Weighted Citation Impact
- 5.15
Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Multidisciplinary University Research Initiative
- National Institute of Environmental Health Sciences
- Army Research Office
- Institute for Collaborative Biotechnologies