Human cytomegalovirus directly modulates expression of chemokine CCL2 (MCP-1) during viral replication
Human cytomegalovirus directly modulates expression of chemokine CCL2 (MCP-1) during viral replication
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DOI：
10.1099/vir.0.052878-0
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发表时间：
2013-11-01
影响因子：
3.8
通讯作者：
Rawlinson, William D.
中科院分区：
文献类型：
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作者：
Hamilton, Stuart T.;Scott, Gillian M.;Rawlinson, William D.
人类巨细胞病毒 (CMV) 感染单核细胞和其他造血祖细胞，然后这些细胞充当潜伏和病毒传播的储存库。趋化因子 CCL2（单核细胞趋化蛋白-1 或 MCP-1）对单核细胞表现出有效的趋化活性，并且可能是 CMV 诱导的免疫调节的靶标。在这项研究中，我们证明CMV以多重依赖性动力学调节MRC-5成纤维细胞中的CCL2表达，其中CCL2在早期感染期间上调，随后在感染晚期抑制CCL2。这种 CMV 诱导的 CCL2 调节依赖于病毒复制，因为紫外线灭活的病毒不会引起 CCL2 水平的任何变化。双重免疫荧光染色显示，CMV 毒株 AD169、纯化的 AD169、Merlin、FIX WT (FLAG-US28/WT) 和 pUS28 缺陷型 FIX (FIX-Delta US28) 均主要在感染细胞内诱导 CCL2 上调。 FIX-Delta US28 感染细胞内 CCL2 的局部上调表明细胞内 CCL2 积累与 CMV 编码趋化因子受体 US28 的 CCL2 隔离无关。纯化病毒感染证实 CMV 诱导的 CCL2 上调并非由于非纯化病毒母液中包含的任何 CCL2 诱导因子所致。 CMV 诱导的 CCL2 表达动力学与 CCL2 转录激活剂 NF-κ B、干扰素调节因子 3 和细胞因子 IFN-β 的调节同时发生，与病毒株无关，并且与受感染细胞核内病毒复制区室的建立同时发生。据我们所知，这是第一份证明 CMV 在病毒复制过程中受感染细胞内 CCL2 表达调节的报告。这种免疫调节可能促进病毒传播、潜伏期的建立和 CMV 诱导的宿主疾病的发病机制。
Human cytomegalovirus (CMV) infects monocytes and other haematopoietic progenitor cells which then act as reservoirs for latency and virus dissemination. The chemokine CCL2 (monocyte chemotactic protein-1 or MCP-1) exhibits potent chemotactic activity for monocytes and is a likely target for CMV-induced immunomodulation. In this study, we demonstrate CMV modulates CCL2 expression in MRC-5 fibroblasts with multiplicity-dependent kinetic's, where CCL2 is upregulated during early stage infection, followed by CCL2 inhibition at late stage infection. This CMV-induced CCL2 modulation was dependent upon virus replication, as UV-inactivated virus did not elicit any changes in CCL2 levels. Dual immunofluorescence staining showed CMV strains AD169, purified AD169, Merlin, FIX WT (FLAG-US28/WT) and pUS28-deficient FIX (FIX-Delta US28) all induced upregulation of CCL2 primarily within infected cells. Focal upregulation of CCL2 within FIX-Delta US28-infected cells demonstrated intracellular CCL2 accumulation was independent of CCL2 sequestration by the CMV-encoded chemokine receptor US28. Infection with purified virus confirmed CMV-induced CCL2 upregulation was not due to any CCL2-inducing factors contained within non-purified virus stocks. The CMV-induced CCL2 expression kinetics occurred concurrently with modulation of the CCL2 transcriptional activators NF-kappa B, interferon regulatory factor 3 and cytokine IFN-beta, independent of virus strain, and with the establishment of viral replication compartments within infected cell nuclei. This is the first report to our knowledge to demonstrate CMV modulation of CCL2 expression within infected cells during viral replication. This immune modulation may facilitate virus dissemination, establishment of latency and pathogenesis of CMV-induced host disease.