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The most distinctive clinical manifestations, such as sustained fever with relative bradycardia, leukopenia, neuropsychiatric symptoms\/encephalopathy, and ileal perforation, have long lacked a unifying mechanistic explanation. Over the past two decades, studies of typhoid toxin have reframed how we understand this disease. Typhoid toxin is a human-adapted, chimeric A\n                    <jats:sub>2<\/jats:sub>\n                    B\n                    <jats:sub>5<\/jats:sub>\n                    exotoxin assembled exclusively inside infected cells. It couples an ADP-ribosyltransferase (PltA) and a DNase I-like nuclease (CdtB) on a pentameric delivery ring (PltB or the alternate, PltC), that recognizes N-acetylneuraminic acid (Neu5Ac)-terminated human sialoglycans. The toxin is produced by bacteria residing within the\n                    <jats:italic toggle=\"yes\">Salmonella<\/jats:italic>\n                    -containing vacuole (SCV), secreted across the bacterial envelope into the SCV lumen by a phage-derived pathway now classified as type 10 secretion system, sorted for export by the host CI-M6PR\/COPII trafficking machinery, and then re-enters distant target cells via retrograde transport to the endoplasmic reticulum (ER). Recent work has linked typhoid toxin to leukopenia, blood-brain barrier disruption causing encephalopathy, gut-vascular and immune dysfunction leading to intestinal perforation, and hepatobiliary injury. The discovery of an alternate B-subunit (PltC) established a paradigm of modular B-subunit exchange that diversifies receptor usage, tissue tropism, and biology. Collectively, these insights redefine typhoid fever as a toxin-driven immunovascular disease and identify actionable targets for neutralizing antibodies and barrier-protective therapies.\n                  <\/jats:p>","DOI":"10.1128\/mmbr.00008-25","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T13:00:41Z","timestamp":1777294841000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Typhoid toxin: reframing enteric fever"],"prefix":"10.1128","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6531-0355","authenticated-orcid":true,"given":"Jorge E.","family":"Gal\u00e1n","sequence":"first","affiliation":[{"name":"Department of Microbial Pathogenesis, Yale School of Medicine","place":["New Haven, 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