Innate immune responses to cytomegalovirus infection in the developing mouse brain and their evasion by virus-infected neurons
Innate immune responses to cytomegalovirus infection in the developing mouse brain and their evasion by virus-infected neurons
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DOI：
10.1016/s0002-9440(10)64252-6
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发表时间：
2002-09-01
影响因子：
6
通讯作者：
Tsutsui, Y
中科院分区：
文献类型：
--
作者：
Kosugi, I;Kawasaki, H;Tsutsui, Y
巨细胞病毒（CMV）是人类发育性脑疾病最常见的感染性原因。在这里，我们展示了自然杀伤细胞（NK）和来自脑巨噬细胞的一氧化氮（NO）在小鼠CMV （MCMV）感染发育中的大脑过程中引起的先天免疫反应的作用。通过NK细胞特异性抗asialo- gm1抗体或NO合成酶2 （NOS2）特异性抑制剂L-N6-（1-亚胺乙基）-赖氨酸，新生小鼠大脑中的病毒复制显著增强。这些结果表明NK细胞和NO有助于大脑病毒的清除。感染后3天（dpi）在脑室周围区免疫组化检测到MCMV早期抗原（Ag）阳性细胞，其中大部分阳性细胞为巨噬细胞。7 dpi时，MCMV-Ag不仅存在于脑室周围区细胞中，还存在于海马和皮层神经元中。11 dpi时，MCMV-Ag在脑室周围区域消失，但在神经元中持续存在。在心室周围区域，NK细胞和nos2阳性巨噬细胞与mcmv - ag阳性细胞相关。相反，mcmv - ag阳性神经元周围很少有NK细胞和nos2阳性巨噬细胞。MCMV DNA原位杂交显示阳性信号主要出现在脑室周围细胞，很少出现在神经元中。这些结果表明，先天免疫反应仅限于复制病毒的细胞，而不影响mcmv感染的神经元。因此，mcmv感染的神经元逃避先天免疫反应可能是支持病毒在发育中的大脑中持续存在的一个重要因素。
Cytomegalovirus (CMV) is the most frequent infectious cause of developmental brain disorders in humans. Here we show the role of innate immune responses caused by natural killer (NK) cells and nitric oxide (NO) derived from brain macrophages during murine CMV (MCMV) infection of the developing brain. Viral replication in the brain of newborn mice was significantly enhanced by administration of anti-asialo-GM1 antibody, specific for NK cells, or L-N6-(1-imminoethyl)-lysine, a specific inhibitor of NO synthase 2 (NOS2). These results suggest that NK cells and NO contribute to the viral clearance from the brain. At 3 days postinfection (dpi) MCMV early antigen (Ag)-positive cells were immunohistochemically detected in the periventricular area, where most of the positive cells were macrophages. At 7 dpi MCMV-Ag was found not only in cells of the periventricular area but also in neurons of the hippocampus and cortex. At 11 dpi MCMV-Ag disappeared from the periventricular area, but persisted in neurons. In the periventricular area, NK cells and NOS2-positive macrophages were associated with MCMV-Ag-positive cells. In contrast, there were very few NK cells and NOS2-positive macrophages around the MCMV-Ag-positive neurons. In situ hybridization for MCMV DNA demonstrated that positive signals were found mostly in the periventricular cells, and rarely in neurons. These results suggest that the innate immune responses are restricted to the virus-replicating cells, and do not affect MCMV-infected neurons. Therefore, evasion of the innate immune responses by MCMV-infected neurons may be an important factor in supporting the viral persistence in the developing brain.