Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease in Fah^−/−, Rag2^−/−, and Il2rɣ^−/− mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.

黄热病 (YF) 是一种由蚊子传播的病毒性疾病，尽管长期部署了有效的疫苗，但每年仍会导致数万人死亡。在最严重的形式中，黄热病表现为一种对内脏器官造成严重损害的出血热。尽管凝血病是人类严重黄热病的一个决定性特征，但其发展机制仍不确定。肝细胞是黄热病病毒 (YFV) 感染的主要目标，长期以来，严重黄热病的凝血功能障碍一直归因于大量肝细胞感染和破坏，导致凝血因子合成缺陷。然而，当我们分析巴西严重 YF 患者的血液时，我们发现高浓度的血浆 D-二聚体（一种纤维蛋白分裂产物）表明存在并发消耗过程。F ah ^-/- , R ag2 ^-/- , 和Il2r ɣ ^-/-使用高致病性非洲 YFV 株移植了人类肝细胞的小鼠（hFRG 小鼠）和恒河猴。根据病毒学、临床和病理学标准，猕猴和 hFRG 小鼠的 YFV 感染会导致大量肝细胞感染、肝损伤和凝血障碍。然而，只有猕猴出现消耗性凝血病，而 YFV 感染的 hFRG 小鼠则没有。因此，肝细胞以外的细胞类型的感染可能导致与灵长类动物和人类严重 YF 相关的消耗性凝血病。这些发现扩大了我们对病毒性出血性疾病和相关凝血病的理解，并为严重 YF 病例的临床管理提出了方向。