Coronaviruses induce entry-independent, continuous macropinocytosis.
Coronaviruses induce entry-independent, continuous macropinocytosis.
复制标题
冠状病毒诱导独立的连续大型细胞增多症。
DOI：
10.1128/mbio.01340-14
复制
发表时间：
2014-08-05
期刊：
影响因子：
6.4
通讯作者：
Denison MR
中科院分区：
文献类型：
--
作者：
Freeman MC;Peek CT;Becker MM;Smith EC;Denison MR
许多病原体利用巨胞饮作用进入细胞。冠状病毒（CoV）如严重急性呼吸综合征（SARS）CoV和中东呼吸综合征CoV是重要的人类病原体;然而，尚未研究CoV感染期间的巨胞饮作用。我们证明，冠状病毒SARS冠状病毒和小鼠肝炎病毒（MHV）诱导巨胞饮，这发生在感染后期，是连续的，是不相关的病毒进入。MHV诱导的巨胞饮导致囊泡内化，以及能够与远处细胞融合的延长的丝状伪足。MHV诱导的巨胞饮作用需要细胞表面的融合刺突蛋白，并依赖于表皮生长因子受体的激活。抑制巨胞饮作用可降低上清液病毒滴度和合胞体，但不降低细胞内病毒滴度。这些结果表明，巨胞饮作用可能通过增强细胞间传播促进CoV感染。我们的研究是第一个证明病毒使用巨胞饮的作用以外的进入，并建议一个更广泛的潜在利用巨胞饮在病毒复制和宿主相互作用。冠状病毒（Coronaviruses，CoV），包括严重急性呼吸综合征（severe acute respiratory syndrome，SARS）CoV和中东呼吸综合征CoV，是重要的新兴人类病原体。巨胞饮作用是由许多病原体诱导进入宿主细胞，但巨胞饮在病毒复制中的其他功能尚不清楚。在这项工作中，我们表明，冠状病毒诱导巨胞饮感染后期是连续的，独立于细胞进入，并与增加的病毒滴度和细胞融合。小鼠肝炎病毒巨胞饮作用需要融合病毒刺突蛋白，并通过表皮生长因子受体和经典巨胞饮途径进行信号传导。这些研究表明，CoV诱导巨胞饮的目的不是进入，并表明病毒可能在复制和发病机制的多个步骤中利用巨胞饮。
Macropinocytosis is exploited by many pathogens for entry into cells. Coronaviruses (CoVs) such as severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV are important human pathogens; however, macropinocytosis during CoV infection has not been investigated. We demonstrate that the CoVs SARS CoV and murine hepatitis virus (MHV) induce macropinocytosis, which occurs late during infection, is continuous, and is not associated with virus entry. MHV-induced macropinocytosis results in vesicle internalization, as well as extended filopodia capable of fusing with distant cells. MHV-induced macropinocytosis requires fusogenic spike protein on the cell surface and is dependent on epidermal growth factor receptor activation. Inhibition of macropinocytosis reduces supernatant viral titers and syncytia but not intracellular virus titers. These results indicate that macropinocytosis likely facilitates CoV infection through enhanced cell-to-cell spreading. Our studies are the first to demonstrate virus use of macropinocytosis for a role other than entry and suggest a much broader potential exploitation of macropinocytosis in virus replication and host interactions. Coronaviruses (CoVs), including severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV, are critical emerging human pathogens. Macropinocytosis is induced by many pathogens to enter host cells, but other functions for macropinocytosis in virus replication are unknown. In this work, we show that CoVs induce a macropinocytosis late in infection that is continuous, independent from cell entry, and associated with increased virus titers and cell fusion. Murine hepatitis virus macropinocytosis requires a fusogenic virus spike protein and signals through the epidermal growth factor receptor and the classical macropinocytosis pathway. These studies demonstrate CoV induction of macropinocytosis for a purpose other than entry and indicate that viruses likely exploit macropinocytosis at multiple steps in replication and pathogenesis.