The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex.
The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex.
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鼠巨细胞病毒的病毒趋化因子MCK-2作为GH/GL/MCK-2复合物的一部分促进感染。
DOI：
10.1371/journal.ppat.1003493
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Adler B
中科院分区：
文献类型：
--
作者：
Wagner FM;Brizic I;Prager A;Trsan T;Arapovic M;Lemmermann NA;Podlech J;Reddehase MJ;Lemnitzer F;Bosse JB;Gimpfl M;Marcinowski L;MacDonald M;Adler H;Koszinowski UH;Adler B
人巨细胞病毒（HCMV）形成两种gH/gL糖蛋白复合物，gH/gL/gO和gH/gL/pUL（128，130，131 A），其决定病毒的嗜性、进入途径和传播模式。对于作为HCMV模型的鼠巨细胞病毒（MCMV），已经描述了与HCMV gH/gL/gO复合物功能同源的gH/gL/gO复合物。MCMV gO的敲除确实损害但不消除病毒传播，表明MCMV也可能形成替代的gH/gL复合物。在这里，我们表明MCMV CC趋化因子MCK-2与糖蛋白gH形成复合物，该复合物被掺入病毒体中。我们还可以证明缺乏gO和MCK-2的突变体不能产生感染性病毒。这些双突变体与gO或MCK-2的反式互补表明，这两种蛋白质都可以促进宿主细胞的感染，尽管是通过不同的进入途径。MCK-2已经被其他人在体内进行了广泛的研究。它已被证明参与吸引细胞进行病毒传播和调节抗病毒宿主反应。我们现在表明，MCK-2，通过与GH形成复合物，在体外和体内强烈促进巨噬细胞的感染。因此，MCK-2可能在MCMV感染中发挥双重作用，作为调节宿主反应和吸引特异性靶细胞的趋化因子，以及作为促进进入病毒传播关键细胞的糖蛋白复合物的一部分。几种人类疱疹病毒形成可选择的gH/gL复合物，其决定了对不同细胞类型的嗜性。对于鼠巨细胞病毒（MCMV），最近已表征了gH/gL/gO复合物。在这里，我们提出了一种替代的gH/gL/MCK-2复合物，促进MCMV传播，是重要的有效感染的巨噬细胞在体外和体内的鉴定和表征。MCMV CC趋化因子MCK-2与促进病毒进入的糖蛋白复合物的关联是充分表征的MCK-2的新功能。已显示缺乏MCK-2的病毒突变体在体内表现出吸引白细胞的能力降低和MCMV感染的T细胞控制失调。这些缺陷可归因于MCK-2的趋化因子功能。然而，MCK-2敲除突变体在体内感染白细胞时另外受损的观察结果与我们的新发现一致，即MCK-2形成促进进入单核细胞的糖蛋白复合物。与多功能蛋白质相关的gH/gL复合物为解释相应敲除疱疹病毒的感染表型增加了新的复杂性。
Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination. Several human herpesviruses form alternative gH/gL complexes which determine the tropism for different cell types. For murine cytomegalovirus (MCMV), a gH/gL/gO complex has recently been characterized. Here, we present the identification and characterization of an alternative gH/gL/MCK-2 complex which promotes MCMV spread and is important for efficient infection of macrophages in vitro and in vivo. Association of the MCMV CC chemokine MCK-2 with a glycoprotein complex promoting virus entry is a novel function for the well-characterized MCK-2. Virus mutants lacking MCK-2 have been shown to exhibit a reduced capacity to attract leukocytes and a disregulated T cell control of the MCMV infection in vivo. These defects can be attributed to the chemokine function of MCK-2. Yet, the observation that MCK-2 knock-out mutants additionally are impaired in infecting leukocytes in vivo is consistent with our new finding that MCK-2 forms a glycoprotein complex promoting entry into monocytic cells. gH/gL complexes associating with multifunctional proteins add a new level of complexity to the interpretation of infection phenotypes of the respective knock-out herpesviruses.
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