Ferret animal model of severe fever with thrombocytopenia syndrome phlebovirus for human lethal infection and pathogenesis

Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the WHO most dangerous pathogens, has 12-30% fatality rates with a characteristic thrombocytopenia syndrome. With a majority of clinically diagnosed SFTSV patients older than ~50 years, age is a critical risk factor for SFTSV morbidity and mortality. Here, we report an age-dependent ferret model of SFTSV infection and pathogenesis that fully recapitulates the clinical manifestations of human infections. While young adult ferrets (≤2 years old) did not show any clinical symptoms and mortality, SFTSV-infected aged ferrets (≥4 years old) demonstrated severe thrombocytopenia, reduced white blood cells, and high fever with 93% mortality rate. Moreover, significantly higher viral load was observed in aged ferrets. Transcriptome analysis of SFTSV-infected young ferrets revealed strong interferon-mediated anti-viral signaling, whereas inflammatory immune responses were markedly upregulated and persisted in aged ferrets. Thus, this immunocompetent age-dependent ferret model should be useful for anti-SFTSV therapy and vaccine development.

发热伴血小板减少综合征布尼亚病毒（Severe fever with thrombocytopenia syndrome phlebovirus, SFTSV）已被列入世界卫生组织（World Health Organization, WHO）的最危险病原体名单，其病死率为12%~30%，以典型的血小板减少综合征为临床特征。临床确诊的SFTSV患者多集中于50岁以上人群，年龄是该病发病与死亡的关键危险因素。本研究报道了一种年龄依赖性的SFTSV感染与发病雪貂模型，该模型可完全复现人类感染后的临床表现。感染后的年轻成年雪貂（≤2岁）未表现出任何临床症状与死亡现象，而感染SFTSV的老年雪貂（≥4岁）则出现严重血小板减少、白细胞计数降低及高热症状，病死率高达93%。此外，老年雪貂体内的病毒载量显著升高。对感染SFTSV的年轻雪貂进行转录组分析发现，其体内存在强烈的干扰素介导的抗病毒信号通路激活；而老年雪貂体内的炎症性免疫应答则被显著上调且持续存在。综上，这一免疫功能健全的年龄依赖性雪貂模型将为抗SFTSV治疗及疫苗研发提供重要的研究工具。