Typhoid toxin primes mouse blood vessels for fatal intestinal perforation

The work is published in Nature Microbiology.

Intestinal perforation is a late complication of typhoid fever and its leading cause of death, yet its mechanism has remained undefined. In the new model, systemic exposure to the toxin establishes a transient priming state in the vascular endothelium, the lining of blood vessels. When the mice are then infected orally, this priming leads to vascular injury, haemorrhage and lethal intestinal perforation, with lesions localized to Peyer’s patches, the immune structures of the small intestine. The lesions were accompanied by the appearance of microbiota-derived bacterial taxa in the blood, consistent with translocation across a breached small-intestinal barrier.

Experiments with mutant Salmonella strains pinpointed which bacterial weapons drive the lethality. Death required the SPI-1 type-III secretion system, which drives intestinal inflammation, but not the SPI-2 type-III secretion system, which drives systemic infection. The authors conclude that the mice died from intestinal rather than disseminated infection, and that systemic proliferation of S. Typhi was not associated with lethality.

The study also clarified what the priming step actually involves. Although PltC-typhoid toxin causes leucopaenia, the loss of circulating white blood cells was not sufficient to sensitize the animals, pointing instead to a direct effect on the endothelium. Supporting this, endothelial-specific expression of CMAH, an enzyme that masks the toxin’s Neu5Ac receptors, prevented both priming and disease. On the basis of these findings, the researchers define intestinal perforation as a typhoid toxin-dependent vascular-barrier disease, in which circulating toxin prepares the vessel lining so that subsequent intestinal infection can breach the barrier. The findings come from mouse experiments and describe a model of late-stage human typhoid; the authors note that in this model circulating toxin precedes the onset of intestinal pathology, mirroring the sequence they propose for the human disease.

Subject of Research: Mechanism of typhoid toxin-dependent intestinal perforation during Salmonella Typhi infection

Article Title: Systemic exposure to typhoid toxin primes the murine vascular endothelium for intestinal perforation during Salmonella Typhi infection

Article References: Zhao, H., Hua, C., Hur, J. I., Lara-Tejero, M., & Galán, J. E. (2026). Systemic exposure to typhoid toxin primes the murine vascular endothelium for intestinal perforation during Salmonella Typhi infection. Nature Microbiology. https://doi.org/10.1038/s41564-026-02521-1

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02521-1

Keywords: typhoid fever, typhoid toxin, Salmonella Typhi, intestinal perforation, vascular endothelium, Peyer's patches, SPI-1 T3SS, SPI-2 T3SS, CMAH, gut barrier, Nature Microbiology, mouse model