Lafoux Blaise, Baillet Nicolas, Picard Caroline, Fourcaud Gustave, Borges-Cardoso Virginie, Reynard Stéphanie, Journeaux Alexandra, Germain Clara, Perthame Emeline, Mateo Mathieu, Hortion Jimmy, Carnec Xavier, Pietrosemoli Natalia, Moroso Marie, Lacroix Orianne, Jourjon Ophélie, Barron Stéphane, Vallve Audrey, Duthey Aurélie, Jacquot Frédéric, Barrot Laura, Dirheimer Manon, Raoul Hervé, Nougier Christophe, Baize Sylvain
Unité de Biologie des Infections Virales Emergentes, Institut Pasteur, Lyon, France.
Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique UMR5308, Lyon, France.
Blood. 2023 Dec 14;142(24):2092-2104. doi: 10.1182/blood.2023020351.
Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although 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 it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause 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 cutaneomucosal, 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.
病毒性出血热（HF）是一组具有高死亡率的急性发热性疾病。尽管止血功能障碍似乎是疾病严重程度的主要决定因素，但导致该障碍的致病机制仍不清楚。在临床研究中发现，诸如拉沙病毒、马丘波病毒和瓜纳里托病毒等沙粒病毒会引发症状和生物学改变各异的出血热。在本研究中，我们旨在描述沙粒病毒所致出血热引起的止血功能障碍，以确定其在疾病严重程度中的作用，并阐明该综合征的起源。我们发现，感染致死剂量的马丘波病毒、瓜纳里托病毒和拉沙病毒与皮肤黏膜、脑、消化道和肺部出血有关。受感染动物的凝血系统出现严重改变，同时伴有急性肝炎、肝脏因子合成轻度不足、血浆凝血抑制剂的存在以及纤维蛋白溶解系统功能障碍。尽管有血管通透性增加的迹象，但内皮细胞感染并非出血综合征的决定因素。在致死性感染期间，初级止血也出现改变，伴有中度至重度血小板减少和血小板功能障碍。最后，我们表明致死性感染伴随着骨髓造血潜能的降低。本研究对几种高致病性沙粒病毒引起的止血缺陷进行了前所未有的描述。
