The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells.
The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells.
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DOI：
10.1371/journal.pone.0152134
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pöhlmann S
中科院分区：
文献类型：
--
作者：
Hoffmann M;Krüger N;Zmora P;Wrensch F;Herrler G;Pöhlmann S
新世界蝙蝠最近被发现携带甲型流感病毒（FLUAV）相关病毒，称为蝙蝠相关甲型流感病毒（bat-associated influenza A-like viruses，batFLUAV）。batFLUAV的内部蛋白质在哺乳动物细胞中具有功能。相比之下，对于表面蛋白，血凝素（HA）样（HAL）和神经氨酸酶（NA）样（NAL），不能证明生物功能性，并且这些蛋白质需要被它们的人类对应物替换以允许batFLUAV在人类细胞中扩散。在这里，我们采用弹状病毒载体，以研究HAL和NAL在病毒进入的作用。用batFLUAV-HAL和-NAL假型化的载体能够进入蝙蝠细胞，但不能进入来自其他哺乳动物物种的细胞。宿主细胞的进入是由HAL介导的，并且依赖于HAL的蛋白水解激活和内体低pH。相反，唾液酸对于HAL驱动的进入是必需的。最后，II型跨膜丝氨酸蛋白酶TMPRSS 2能够激活HAL以进入细胞，表明batFLUAV可以利用人蛋白酶来激活HAL。总的来说，这些结果鉴定了由batFLUAV表面蛋白驱动的控制宿主细胞进入的病毒和细胞因子。他们认为，功能性受体的缺乏阻止了batFLUAV进入人细胞，而进入的其他先决条件，HAL激活和质子化，在人源的靶细胞中得到满足。
New World bats have recently been discovered to harbor influenza A virus (FLUAV)-related viruses, termed bat-associated influenza A-like viruses (batFLUAV). The internal proteins of batFLUAV are functional in mammalian cells. In contrast, no biological functionality could be demonstrated for the surface proteins, hemagglutinin (HA)-like (HAL) and neuraminidase (NA)-like (NAL), and these proteins need to be replaced by their human counterparts to allow spread of batFLUAV in human cells. Here, we employed rhabdoviral vectors to study the role of HAL and NAL in viral entry. Vectors pseudotyped with batFLUAV-HAL and -NAL were able to enter bat cells but not cells from other mammalian species. Host cell entry was mediated by HAL and was dependent on prior proteolytic activation of HAL and endosomal low pH. In contrast, sialic acids were dispensable for HAL-driven entry. Finally, the type II transmembrane serine protease TMPRSS2 was able to activate HAL for cell entry indicating that batFLUAV can utilize human proteases for HAL activation. Collectively, these results identify viral and cellular factors governing host cell entry driven by batFLUAV surface proteins. They suggest that the absence of a functional receptor precludes entry of batFLUAV into human cells while other prerequisites for entry, HAL activation and protonation, are met in target cells of human origin.