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

Intestinal perforation is a late complication and the leading cause of death in typhoid fever, but its mechanism has remained undefined. Here, using sequential exposure to the PltC form of typhoid toxin followed by oral Salmonella Typhi infection, we develop a mouse model of late-stage human typhoid, when circulating toxin precedes the onset of intestinal pathology. Systemic exposure to the toxin renders otherwise resistant mice susceptible to oral infection and establishes a transient vascular endothelial priming state, resulting in vascular injury, haemorrhage and lethal intestinal perforation localized to Peyer's patches. These lesions were accompanied by the appearance in blood of microbiota-derived taxa, consistent with translocation across a breached small-intestinal barrier. Lethality required the SPI-1 type-III secretion system (T3SS), which drives intestinal inflammation, but not the SPI-2 T3SS, which drives systemic infection, indicating that death results from intestinal rather than disseminated infection. Although PltC-typhoid toxin causes leucopaenia, loss of circulating white cells was not sufficient for sensitization. Endothelial-specific expression of CMAH, which masks the toxin's Neu5Ac receptors, prevented priming and disease. These findings define intestinal perforation as a typhoid toxin-dependent vascular-barrier disease.