角色的公认的人类metapneumovirus integrin-binding图案融合(f)蛋白在信息融合,病毒性传染性和发病机理。
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张魏Y, Y, Cai H,殿下,人工RM,皮尔普斯我,李Niewiesk年代,J
角色的公认的人类metapneumovirus integrin-binding图案融合(f)蛋白在信息融合,病毒性传染性和发病机理。
J微生物学报。2014年4月,88 (8):4338 - 52。doi: 10.1128 / JVI.03491-13。Epub 2014年1月29日。
- PubMed ID
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24478423 (在PubMed]
- 文摘
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人类metapneumovirus (hMPV)是最近确定副粘病毒引起急性上下呼吸道感染。进入hMPV地利亚是不寻常的,在融合是通过融合(F)蛋白质没有附件糖蛋白(G蛋白)。有人建议,hMPV F蛋白利用整合素alphavbeta1细胞受体。与此一致的是,所有已知的hMPV F蛋白的菌株具有一个integrin-binding主题((329)RGD (331))。这个主题在病毒进入的作用,传染性和发病机制了解甚少。在这里,我们表明,alpha5beta1和alphav整合蛋白信息融合和hMPV感染至关重要。突变分析发现残留R329和G330 (329) RGD(331)的主题和信息融合至关重要,而突变在D331融合活动没有显著影响。此外,fusion-defective RGD突变都是致命的病毒或导致重组hMPVs缺陷病毒复制的细胞培养。棉花的老鼠,重组hMPV R329K F蛋白的突变(rhMPV-R329K)和rhMPV-D331A方面表现出显著的缺陷在鼻鼻甲骨和肺病毒复制。重要的是,接种的棉花老鼠与这些突变体引发了一场高水平的中和抗体和防止hMPV挑战。 Taken together, our data indicate that (i) alpha5beta1 and alphav integrins are essential for cell-cell fusion and viral replication, (ii) the first two residues in the RGD motif are essential for fusion activity, and (iii) inhibition of the interaction of the integrin-RGD motif may serve as a new target to rationally attenuate hMPV for the development of live attenuated vaccines. IMPORTANCE: Human metapneumovirus (hMPV) is one of the major causative agents of acute respiratory disease in humans. Currently, there is no vaccine or antiviral drug for hMPV. hMPV enters host cells via a unique mechanism, in that viral fusion (F) protein mediates both attachment and fusion activity. Recently, it was suggested that hMPV F protein utilizes integrins as receptors for entry via a poorly understood mechanism. Here, we show that alpha5beta1 and alphav integrins are essential for hMPV infectivity and F protein-mediated cell-cell fusion and that the integrin-binding motif in the F protein plays a crucial role in these functions. Our results also identify the integrin-binding motif to be a new, attenuating target for the development of a live vaccine for hMPV. These findings not only will facilitate the development of antiviral drugs targeting viral entry steps but also will lead to the development new live attenuated vaccine candidates for hMPV.