Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

Abstract

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.

Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma

“…In severe haemorrhagic diathesis, as observed in YF, an extremely harmful environment is built with the marked presence of an altered (lesion in the) vascular endothelium, which plays a role in adhesion molecules, cytokine storm, and the intense recruitment of defence cells triggered in the organ in response to viral aggression. Taken together, with the intense and severe in situ damage, our results strongly suggest the occurrence of a massive hepatic propagation injury that culminates in consumptive coagulopathy and haemorrhagic manifestations classic to the fatal outcome of the disease [13].…”

Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma

“…In severe haemorrhagic diathesis, as observed in YF, an extremely harmful environment is built with the marked presence of an altered (lesion in the) vascular endothelium, which plays a role in adhesion molecules, cytokine storm, and the intense recruitment of defence cells triggered in the organ in response to viral aggression. Taken together, with the intense and severe in situ damage, our results strongly suggest the occurrence of a massive hepatic propagation injury that culminates in consumptive coagulopathy and haemorrhagic manifestations classic to the fatal outcome of the disease [13]. Institutional Review Board Statement: The study was conducted in accordance with the 1964 Helsinki 254 Declaration and later versions.…”

Isolation of a potently neutralizing and protective human monoclonal antibody targeting yellow fever virus

“…We recently developed a YFV infection model in mice engrafted with human hepatocytes (hFRG mice) [32]. Immunodeficient hFRG mice have three genetic lesions (fumarylacetoacetate hydrolase [ F ah] -/- , R ag2 -/- , and Il2r ɣ -/- on a C57BL/6J background), which together with specifically-timed dietary modifications, facilitate the durable replacement of murine hepatocytes with transplanted human hepatocytes [33].…”

“…Immunodeficient hFRG mice have three genetic lesions (fumarylacetoacetate hydrolase [ F ah] -/- , R ag2 -/- , and Il2r ɣ -/- on a C57BL/6J background), which together with specifically-timed dietary modifications, facilitate the durable replacement of murine hepatocytes with transplanted human hepatocytes [33]. YFV-infected hFRG mice developed disease that recapitulates many features of YF in humans including massive hepatic infection and injury [32]. Here we tested the therapeutic activity of YFV-136 in this highly susceptible hepatotropic model.…”

“…Welfare Act. Female hFRG mice were generated by Yecuris Corporation and maintained according to their specific care and use guidelines (see [32] for additional details). Only mice with human albumin levels of ≥ 5.0 mg/mL in plasma (indicative of ≥70% engraftment) were used for this study.…”