Center for Public Health Research, Medical School, Nanjing University, Nanjing, China.
School of Life Sciences, Ningxia University, Yinchuan, P.R. China.
PLoS Pathog. 2021 May 11;17(5):e1009587. doi: 10.1371/journal.ppat.1009587. eCollection 2021 May.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne emerging phlebovirus with high mortality rates of 6.0 to 30%. SFTSV infection is characterized by high fever, thrombocytopenia, leukopenia, hemorrhage and multiple organ failures. Currently, specific therapies and vaccines remain elusive. Suitable small animal models are urgently needed to elucidate the pathogenesis and evaluate the potential drug and vaccine for SFTSV infection. Previous models presented only mild or no pathogenesis of SFTS, limiting their applications in SFTSV infection. Therefore, it is an urgent need to develop a small animal model for the investigation of SFTSV pathogenesis and evaluation of therapeutics. In the current report, we developed a SFTSV infection model based on the HuPBL-NCG mice that recapitulates many pathological characteristics of SFTSV infection in humans. Virus-induced histopathological changes were identified in spleen, lung, kidney, and liver. SFTSV was colocalized with macrophages in the spleen and liver, suggesting that the macrophages in the spleen and liver could be the principle target cells of SFTSV. In addition, histological analysis showed that the vascular endothelium integrity was severely disrupted upon viral infection along with depletion of platelets. In vitro cellular assays further revealed that SFTSV infection increased the vascular permeability of endothelial cells by promoting tyrosine phosphorylation and internalization of the adhesion molecule vascular endothelial (VE)-cadherin, a critical component of endothelial integrity. In addition, we found that both virus infection and pathogen-induced exuberant cytokine release dramatically contributed to the vascular endothelial injury. We elucidated the pathogenic mechanisms of hemorrhage syndrome and developed a humanized mouse model for SFTSV infection, which should be helpful for anti-SFTSV therapy and pathogenesis study.
严重发热伴血小板减少综合征病毒（SFTSV）是一种蜱传新兴的黄病毒，死亡率高达 6.0%至 30%。SFTSV 感染的特征是高热、血小板减少、白细胞减少、出血和多器官衰竭。目前，仍然缺乏特异性治疗方法和疫苗。迫切需要合适的小动物模型来阐明发病机制，并评估 SFTSV 感染的潜在药物和疫苗。以前的模型仅表现出轻微或没有 SFTS 的发病机制，限制了它们在 SFTSV 感染中的应用。因此，迫切需要开发一种用于研究 SFTSV 发病机制和评估治疗方法的小动物模型。在本报告中，我们基于 HuPBL-NCG 小鼠开发了一种 SFTSV 感染模型，该模型再现了 SFTSV 感染在人类中的许多病理特征。在脾脏、肺、肾和肝中鉴定出病毒诱导的组织病理学变化。SFTSV 与巨噬细胞在脾脏和肝脏中聚集，表明脾脏和肝脏中的巨噬细胞可能是 SFTSV 的主要靶细胞。此外，组织学分析表明，病毒感染伴随着血小板耗竭，严重破坏了血管内皮的完整性。体外细胞分析进一步表明，SFTSV 通过促进粘着分子血管内皮钙黏蛋白（VE-cadherin）的酪氨酸磷酸化和内化，增加内皮细胞的血管通透性，VE-cadherin 是内皮完整性的关键组成部分。此外，我们发现病毒感染和病原体诱导的细胞因子过度释放都显著导致了血管内皮损伤。我们阐明了出血综合征的发病机制，并开发了一种 SFTSV 感染的人源化小鼠模型，这应该有助于抗 SFTSV 治疗和发病机制研究。
