Mesenteric Ischemia and Bacterial Translocation Precipitate the Intoxication Phase of Yellow Fever

Background 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 extrahepatic disease may be important for the approximately 30% of YF cases that progress to the severe "intoxication"phase of the disease. Methods 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. Results HA-YFV caused severe disease in approximately 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 extrahepatic 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 appears to be a sepsis-like syndrome caused by translocation of bacteria from a damaged gastrointestinal 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 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 nonfatal cases, suggesting that I-FABP measurements could be useful in prognosis and treatment decision-making. Conclusions Our findings tie together several recent and historically unexplained observations surrounding the highly lethal intoxication phase of YF in humans: A high aspartate aminotransferase/alanine aminotransferase 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.