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The study for the immune evasion of developing cerebral neurons infected with cytomegaloviurs

巨细胞病毒感染发育中脑神经元的免疫逃避研究

基本信息

批准号：
16590307
负责人：
KOSUGI Isao
金额：
$ 2.24万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

The role of innate immune responses caused by NK cells and NO derived from brain macrophages during MCMV infection in the developing brains of C57BL/6 mice was investigated. The viral titer of the brains of neonatal mice inoculated with MCMV (half of LD50) peaked at 7 days post-infection (dpi) then declined. Viral replication in the brain of newborn mice was significantly enhanced by administration of anti-asialo-GM1 antibody, a specific inhibitor of NK cells, or L- N6-(1-imminoethyl)-lysine, a specific inhibitor of NO2. Thus, NK cells and NO contribute to viral clearance from the brain. At early phases of infection (3 dpi), the MCMV E1 antigen-positive cells and viral DNA were detected in cells of the lateral ventricle (V). At 7 dpi the E1-positive cells were found not only in cells of the lateral ventricle but also in the neurons of the hippocampus (Hp) and cortex (Cx). At a prolonged phase of infection (11 dpi), the E1-positive cells disap- peared from the ventricular wall, but pers … More isted in neurons (Figure 6A). At 7 dpi, in the ventricular wall, a GM1 (NK cell marker), NOS (macrophage marker) were expressed markedly, whereas in the hippocampus, although the E1 antigen was expressed in neurons, the markers of NK cells and macrophages were hardly expressed. Viral DNA was also hardly detected in neurons of the hippocampus.It is hypothesised that some signals from the infected cells in the ventricular walls activate NK cells and macrophages. INF from NK cells may induce NOS in macrophages, then cytokines such as IL12 from the activated macrophages activate NK cells, resulting in lysis of the infected cells. In contrast, the prolonged infected neurons in the hippocampus may evade the innate immunity and transfer to persistent infection. It has been reported that innate immune responses begin with the recognition of MCMV-infected cells by NK cells via the interaction between the Ly49H molecule of NK cells and the m157 protein of MCMV on virus-infected cells. It is possible that expression of m157 proteins as ligands for Ly49 receptor of NK cells may be insufficient in MCMV-infected neurons to induce the innate immune response. Less

研究了NK细胞和脑巨噬细胞来源NO在MCMV感染C57BL/6小鼠发育脑中的先天免疫应答作用。接种MCMV的新生小鼠大脑病毒滴度在感染后7天达到峰值（LD50的一半），然后下降。通过NK细胞特异性抑制剂抗asialo- gm1抗体或NO2特异性抑制剂L- N6-（1-亚胺乙基）-赖氨酸，新生小鼠脑内的病毒复制显著增强。因此，NK细胞和NO有助于清除大脑中的病毒。感染早期（3 dpi），侧脑室(V)细胞中检测到MCMV E1抗原阳性细胞和病毒DNA。7 dpi时，除了侧脑室细胞外，海马神经元（Hp）和皮质神经元（Cx）也有e1阳性细胞。在感染的延长阶段（11 dpi）， e1阳性细胞从脑室壁上消失，但在神经元中有更多的细胞（图6A）。7 dpi时，脑室壁上GM1 （NK细胞标记物）、NOS（巨噬细胞标记物）显著表达，而海马神经元中E1抗原虽有表达，但NK细胞和巨噬细胞标记物几乎不表达。在海马神经元中也几乎没有检测到病毒DNA。据推测，来自脑室壁感染细胞的一些信号激活了NK细胞和巨噬细胞。NK细胞产生的INF可诱导巨噬细胞产生NOS，被激活的巨噬细胞产生的il - 12等细胞因子激活NK细胞，导致被感染细胞的裂解。相反，海马中受感染时间延长的神经元可能会逃避先天免疫，转移到持续感染。据报道，先天免疫反应始于NK细胞通过NK细胞的Ly49H分子与MCMV的m157蛋白在病毒感染细胞上的相互作用对MCMV感染细胞的识别。在mcmv感染的神经元中，作为NK细胞Ly49受体配体的m157蛋白的表达可能不足以诱导先天免疫反应。少