Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus with a wide host range including ruminants and humans. RVFV outbreaks have had devastating effects on public health and the livestock industry in African countries. However, there is no approved RVFV vaccine for human use in non-endemic countries and no FDA-approved antiviral drug for RVFV treatment. The RVFV 78kDa protein (P78), which is a membrane glycoprotein, plays a role in virus dissemination in the mosquito host, but its biological role in mammalian hosts remains unknown. We generated an attenuated RVFV MP-12 strain-derived P78-High virus and a virulent ZH501 strain-derived ZH501-P78-High virus, both of which expressed a higher level of P78 and carried higher levels of P78 in the virion compared to their parental viruses. We also generated another MP-12-derived mutant virus (P78-KO virus) that does not express P78. MP-12 and P78-KO virus replicated to similar levels in fibroblast cell lines and Huh7 cells, while P78-High virus replicated better than MP-12 in Vero E6 cells, fibroblast cell lines, and Huh7 cells. Notably, P78-High virus and P78-KO virus replicated less efficiently and more efficiently, respectively, than MP-12 in macrophage cell lines. ZH501-P78-High virus also replicated poorly in macrophage cell lines. Our data further suggest that inefficient binding of P78-High virus to the cells led to inefficient virus internalization, low virus infectivity and reduced virus replication in a macrophage cell line. P78-High virus and P78-KO virus showed lower and higher virulence than MP-12, respectively, in young mice. ZH501-P78-High virus also exhibited lower virulence than ZH501 in mice. These data suggest that high levels of P78 expression attenuate RVFV virulence by preventing efficient virus replication in macrophages. Genetic alteration leading to increased P78 expression may serve as a novel strategy for the attenuation of RVFV virulence and generation of safe RVFV vaccines.

中文翻译：

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裂谷热病毒 78kDa 包膜蛋白减弱巨噬细胞衍生细胞系中的病毒复制和小鼠的病毒毒力。

裂谷热病毒 (RVFV) 是一种蚊媒布尼亚病毒，宿主范围广泛，包括反刍动物和人类。RVFV 的爆发对非洲国家的公共卫生和畜牧业产生了破坏性影响。然而，在非流行国家没有批准用于人类使用的 RVFV 疫苗，也没有 FDA 批准的用于 RVFV 治疗的抗病毒药物。RVFV 78kDa 蛋白 (P78) 是一种膜糖蛋白，在蚊子宿主中的病毒传播中起作用，但其在哺乳动物宿主中的生物学作用仍然未知。我们产生了一种减毒的 RVFV MP-12 株衍生的 P78-High 病毒和一种毒力 ZH501 株衍生的 ZH501-P78-High 病毒，与它们相比，这两种病毒都表达了更高水平的 P78 并在病毒粒子中携带了更高水平的 P78。亲本病毒。我们还生成了另一种不表达 P78 的 MP-12 衍生突变病毒（P78-KO 病毒）。MP-12 和 P78-KO 病毒在成纤维细胞系和 Huh7 细胞中的复制水平相似，而 P78-High 病毒在 Vero E6 细胞、成纤维细胞系和 Huh7 细胞中的复制效果优于 MP-12。值得注意的是，P78-High 病毒和 P78-KO 病毒在巨噬细胞系中的复制效率分别低于 MP-12。ZH501-P78-High 病毒在巨噬细胞系中的复制也很差。我们的数据进一步表明，P78-High 病毒与细胞的低效结合导致巨噬细胞系中病毒内化效率低下、病毒感染性低和病毒复制减少。P78-High 病毒和 P78-KO 病毒在年轻小鼠中分别显示出比 MP-12 更低和更高的毒力。ZH501-P78-High 病毒在小鼠中的毒力也低于 ZH501。这些数据表明，高水平的 P78 表达通过阻止病毒在巨噬细胞中的有效复制来减弱 RVFV 的毒力。导致 P78 表达增加的遗传改变可作为减弱 RVFV 毒力和产生安全 RVFV 疫苗的新策略。