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

Yellow fever (YF) is classically conceptualized as a hepatotropic disease; indeed, the liver is the primary site of yellow fever virus (YFV) replication. However, circumstantial evidence suggests that extra-hepatic disease may be important for the [~]30% of YF cases that progress to the severe "intoxication" phase of the disease. Using a Syrian hamster-adapted (HA)-YFV, we worked backwards from observations in humans to examine early events that precipitate the intoxication phase of YF. HA-YFV caused severe disease in [~]80% of infected animals characterized by lethargy and weight loss that progressed to widespread petechiae and death by day 6. Clinical chemistry, coagulation testing, histology, immunohistochemistry, and in-situ hybridization were consistent with a cascade of hepatocyte-specific virus replication causing liver damage and a defect in clotting factor synthesis. Despite a lack of extra-hepatic HA-YFV replication, severe pathology was observed in the intestines and pancreas. Histopathological analysis over the time-course of HA-YFV infection revealed an ischemic pattern in these tissues, culminating in fibrinoid/coagulative necrosis of these organs. Further investigation showed that ischemia-induced erosion of the gut epithelial barrier serves as an entry point for luminal bacteria that spread systemically via the portal system. Thus, the intoxication phase of YF is a sepsis-like syndrome caused by translocation of bacteria from a damaged gastrointestinal tract. Evaluation of human YF cases for these previously overlooked 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 bacteremia and a bacteria-driven inflammatory response. Importantly, blood concentrations of the gastrointestinal damage marker intestinal fatty acid binding protein (I-FABP) were significantly elevated in fatal YF cases relative to non-fatal cases, suggesting that I-FABP measurements could be useful in prognosis and treatment decision making. Our 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. A better appreciation for the drivers of mesenteric ischemia, and preemption of bacterial sepsis, may improve outcomes in cases of severe YF.