Mesenteric ischemia and bacterial translocation precipitate the intoxication phase of yellow fever

A lethality-defining feature of yellow fever (YF) is the development of “intoxication,” a poorly understood late complication of YF that develops in ∼30% of cases characterized by return of fever, lack of viremia, and hemorrhage. Using a hamster model of YF, we worked backwards from observations in humans to examine early events that precipitate the intoxication phase of YF. Severe gastrointestinal damage was a surprising feature of HA-YFV pathology. This was defined by early signs of ischemia followed by ischemia-induced erosion of the gut epithelial barrier, which served as an entry point for luminal bacteria that opportunistically spread via the portal system. Thus, the intoxication phase of YF is a sepsis-like syndrome caused by translocation of bacteria from a damaged intestinal tract. Evaluation of human YF cases for these previously disconnected disease features confirmed this overarching mechanism: bacteria were identified in the portal vein and liver parenchyma of fatal YF cases along with elevations in plasma markers of intestinal damage and bacteremia. These findings tie together several recent and historically unexplained observations surrounding the highly-lethal intoxication phase of YF in humans: a high AST/ALT ratio, “black vomit,” pancreatitis, and paradoxical neutrophilia, with implications for treating and prevent YF intoxication.