Reverse Genetics System for Heartland Bandavirus: NSs Protein Contributes to Heartland Bandavirus Virulence
Reverse Genetics System for Heartland Bandavirus: NSs Protein Contributes to Heartland Bandavirus Virulence
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DOI：
10.1128/jvi.00049-22
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发表时间：
2022-03
影响因子：
5.4
通讯作者：
S. Taniguchi;Takuya Inagaki;S. Tajima;Tadaki Suzuki;T. Yoshikawa;S. Fukushi;Eun-sil Park;Hikaru Fujii-H
中科院分区：
文献类型：
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作者：
S. Taniguchi;Takuya Inagaki;S. Tajima;Tadaki Suzuki;T. Yoshikawa;S. Fukushi;Eun-sil Park;Hikaru Fujii-H
中心带病毒 (HRTV) 是 2009 年在美国发现的一种蜱传病毒。HRTV 会导致人类发烧、疲劳、食欲下降、头痛、恶心、腹泻以及肌肉或关节疼痛。摘要 中心带病毒 (HRTV) 是一种新兴的蜱传病毒，于 2009 年在密苏里州首次发现，会导致人类发烧、疲劳、食欲下降、头痛、恶心、腹泻以及肌肉或关节疼痛。 HRTV 在基因上与大别班达病毒接近，大别班达病毒是人类严重发热伴血小板减少综合征 (SFTS) 的病原体，被称为 SFTS 病毒 (SFTSV)。完全由克隆的 cDNA 产生感染性 HRTV 尚未见报道。 HRTV 反向遗传学系统的缺乏延迟了了解其发病机制以及生产疫苗和抗病毒药物的努力。在这里，我们开发了 HRTV 的反向遗传学系统，该系统采用 RNA 聚合酶 I 介导的表达系统。生成了重组非结构蛋白 (NSs) 敲除 HRTV (rHRTV-NSsKO)。我们发现 NSs 中断了 HRTV 感染细胞中与先天免疫相关的信号传导。 HRTV 感染小鼠模型中明显没有症状表明 rHRTV-NSsKO 高度减毒。此外，用 rHRTV-NSsKO 免疫的小鼠在致命剂量的 HRTV 中存活下来。这些发现表明 NSs 是 HRTV 的毒力因子，rHRTV-NSsKO 可能是 HRTV 的候选疫苗。重要性 心地班达病毒 (HRTV) 是 2009 年在美国发现的一种蜱传病毒。HRTV 会导致人类发烧、疲劳、食欲下降、头痛、恶心、腹泻以及肌肉或关节疼痛。 FDA 批准的疫苗和抗病毒药物尚不可用。反向遗传学系统的缺乏阻碍了开发此类抗病毒疗法的努力。在这里，我们开发了 HRTV 的反向遗传学系统，从而产生了重组非结构蛋白 (NSs) 敲除 HRTV (rHRTV-NSsKO)。我们发现 NSs 中断了 HRTV 感染细胞中与先天免疫相关的信号传导。此外，rHRTV-NSsKO 在小鼠模型中具有高度减毒和免疫原性。这些发现表明 NSs 是 HRTV 的毒力因子，rHRTV-NSsKO 可能是 HRTV 的候选疫苗。
Heartland bandavirus (HRTV) is a tick-borne virus identified in the United States in 2009. HRTV causes fever, fatigue, decreased appetite, headache, nausea, diarrhea, and muscle or joint pain in humans. ABSTRACT Heartland bandavirus (HRTV), which is an emerging tick-borne virus first identified in Missouri in 2009, causes fever, fatigue, decreased appetite, headache, nausea, diarrhea, and muscle or joint pain in humans. HRTV is genetically close to Dabie bandavirus, which is the causative agent of severe fever with thrombocytopenia syndrome (SFTS) in humans and is known as SFTS virus (SFTSV). The generation of infectious HRTV entirely from cloned cDNAs has not yet been reported. The absence of a reverse genetics system for HRTV has delayed efforts to understand its pathogenesis and to generate vaccines and antiviral drugs. Here, we developed a reverse genetics system for HRTV, which employs an RNA polymerase I-mediated expression system. A recombinant nonstructural protein (NSs)-knockout HRTV (rHRTV-NSsKO) was generated. We found that NSs interrupted signaling associated with innate immunity in HRTV-infected cells. The rHRTV-NSsKO was highly attenuated, indicated by the apparent absence of symptoms in a mouse model of HRTV infection. Moreover, mice immunized with rHRTV-NSsKO survived a lethal dose of HRTV. These findings suggest that NSs is a virulence factor of HRTV and that rHRTV-NSsKO could be a vaccine candidate for HRTV. IMPORTANCE Heartland bandavirus (HRTV) is a tick-borne virus identified in the United States in 2009. HRTV causes fever, fatigue, decreased appetite, headache, nausea, diarrhea, and muscle or joint pain in humans. FDA-approved vaccines and antiviral drugs are unavailable. The lack of a reverse genetics system hampers efforts to develop such antiviral therapeutics. Here, we developed a reverse genetics system for HRTV that led to the generation of a recombinant nonstructural protein (NSs)-knockout HRTV (rHRTV-NSsKO). We found that NSs interrupted signaling associated with innate immunity in HRTV-infected cells. Furthermore, rHRTV-NSsKO was highly attenuated and immunogenic in a mouse model. These findings suggest that NSs is a virulence factor of HRTV and that rHRTV-NSsKO could be a vaccine candidate for HRTV.