Cytomegalovirus Initiates Infection Selectively from High-Level β1 Integrin-Expressing Cells in the Brain.
Cytomegalovirus Initiates Infection Selectively from High-Level β1 Integrin-Expressing Cells in the Brain.
复制标题
巨细胞病毒选择性地从大脑中表达高水平 β1 整合素的细胞中引发感染。
DOI：
10.1016/j.ajpath.2015.01.032
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Iwashita T.
中科院分区：
文献类型：
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作者：
Kawasaki H;Kosugi I;Sakao-Suzuki M;Meguro S;Arai Y;Tsutsui Y;Iwashita T.
巨细胞病毒（CMV）是引起先天性异常（如CMV脑炎）的宫内感染中的流行病原体，其特征在于反应性神经胶质增生、反应性单核细胞、小胶质细胞结节和脑室脑炎的局灶性区域。为了阐明CMV易感性在发育中的脑中的机制，研究了CMV感染的细胞嗜性和感染动力学。我们从CMV及其受体（β1整合素）在感染早期的分布角度评价了脑室内和血管内感染。小鼠巨细胞病毒（MCMV）立即早期1-阳性细胞共定位主要与脑膜和脉络丛（脑室内感染后）或与内皮细胞和周细胞（血管内感染后）。使用表达绿色荧光蛋白的重组MCMV颗粒和荧光微珠（100至300 nm），我们发现CMV颗粒大小是决定初始CMV分布的主要因素。使用shRNA和功能性阻断抗体抑制β1整合素可显着减少MCMV感染。IHC分析、流式细胞术和脑切片分析强烈支持高水平β1整合素表达细胞（例如，内皮细胞、周细胞、脑膜、脉络丛和神经干祖细胞）是MCMV的第一靶点。因此，我们的数据表明MCMV颗粒和β1整合素的初始分布决定了急性期脑内感染的不同模式。
Cytomegalovirus (CMV) is a prevalent pathogen in intrauterine infections that causes congenital anomalies such as CMV encephalitis, which is characterized by the focal areas of reactive gliosis, reactive mononuclear cells, microglial nodules, and ventriculoencephalitis. To elucidate the mechanisms of CMV susceptibility in the developing brain, cell tropism and the infectious dynamics of CMV infection were investigated. We evaluated intraventricular and intravascular infections from the perspective of the distribution of CMV and its receptor (β1 integrin) in the earliest phase of infection. Murine CMV (MCMV) immediate early 1–positive cells were colocalized mainly with meninges and choroid plexus (after intraventricular infection) or with endothelial cells and pericytes (after intravascular infection). Using green fluorescent protein–expressing recombinant MCMV particles and fluorescent microbeads (100 to 300 nm), we revealed that CMV particle size is the primary factor determining the initial CMV distribution. β1 Integrin inhibition using a shRNA and functional blocking antibody significantly reduced MCMV infection. IHC analysis, flow cytometric, and brain slice analyses strongly support that high-level β1 integrin–expressing cells (eg, endothelial cells, pericytes, meninges, choroid plexus, and neural stem progenitor cells) are the first targets of MCMV. Therefore, our data demonstrate that the initial distributions of MCMV particles and β1 integrin determine the distinct pattern of infection in the brain in the acute phase.