Hemostasis defects underlying the hemorrhagic syndrome caused by Mammarenaviruses in a cynomolgus macaque model

Abstract: Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. While hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies, arenaviruses such as Lassa, Machupo and Guanarito viruses caused HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito and Lassa viruses is associated with cutaneo-mucosal, cerebral, digestive and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic Arenaviruses. Transcriptomics data presented in Figure 3 and in Supp Figure 2摘要：病毒性出血热（Viral Hemorrhagic Fevers，HF）是一类病死率较高的急性发热性疾病。尽管止血功能异常似乎是决定该病严重程度的关键因素，但其具体致病机制仍不明晰。临床研究显示，拉沙病毒、马丘波病毒及瓜纳里托病毒等沙粒病毒（Arenavirus）可引发HF，此类病例的临床症状与生物学改变存在差异。本研究旨在明确沙粒病毒相关性HF所引发的止血功能异常的特征，以解析其与疾病严重程度的关联，并阐明该综合征的成因。本研究发现，马丘波病毒、瓜纳里托病毒与拉沙病毒的致死性感染，可导致皮肤黏膜、脑部、消化道及肺部出血。受感染动物会出现严重的凝血系统异常，同时伴随急性肝炎、肝脏凝血因子合成轻度不足、血浆凝血抑制物存在以及纤溶系统功能障碍。尽管观察到血管通透性升高的迹象，但内皮细胞感染并非该出血综合征的决定性致病因素。致死性感染期间，初级止血过程亦出现异常，表现为中度至重度血小板减少症与血小板功能异常。最后，本研究证实致死性感染会伴随骨髓造血潜能降低。本研究首次对多种高致病性沙粒病毒所诱导的止血功能缺陷进行了系统性表征。本研究的转录组学（Transcriptomics）数据展示于图3及补充图2（Supp Figure 2）