Reuter Jon D, Gomez Daniel L, Wilson Jean H, Van Den Pol Anthony N
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Virol. 2004 Feb;78(3):1473-87. doi: 10.1128/jvi.78.3.1473-1487.2004.
Cytomegalovirus (CMV) is a significant opportunistic pathogen associated with AIDS and immunosuppressive therapy. Infection of the mature central nervous system (CNS) can cause significant pathology with associated neurological deficits, mental disorders, and cognitive impairment and may have potentially fatal consequences. Using genetically immunocompromised mice, we studied mechanisms of CMV invasion into, and behavior within, the CNS. Adult immunodeficient (nude and SCID) and control mice were peripherally infected with recombinant mouse CMV expressing a green fluorescent protein reporter gene. Control mice actively eliminated acute peripheral infection and were resistant to invasion of CMV into the brain. In contrast, virus infected brains of immunodeficient mice but only after a minimum of 21 days postinoculation. After inoculation, CMV was found in circulating leukocytes (MAC-3/CD45(+)) and in leukocytes within the brain, suggesting these cells as a possible source of CMV entry into the CNS. CNS infection was observed in many different cell types, including neurons, glial cells, meninges, ependymal cells, and cells of cerebral vessels. Infection foci progressively expanded locally to adjacent cells, resulting in meningitis, choroiditis, encephalitis, vasculitis, and necrosis; clear indication of axonal transport of CMV was not found. Regional distribution of CMV was unique in each brain, consisting of randomly distributed, unilateral foci. Testing whether CMV gained access to brain through nonspecific vascular disruption, vascular injections of a tracer molecule revealed no obvious disruption of the blood brain barrier in mice with CMV in the brain. Results indicate the importance of host adaptive immunity (particularly T cells) in controlling entry and dissemination of CMV into the brain and are consistent with the view that virus may be carried into the brain by circulating mononuclear cells that traffic through the blood brain barrier.
巨细胞病毒（CMV）是一种与艾滋病和免疫抑制治疗相关的重要机会性病原体。成熟中枢神经系统（CNS）的感染可导致严重病变，并伴有神经功能缺损、精神障碍和认知障碍，可能产生潜在的致命后果。我们利用基因免疫受损小鼠研究了CMV侵入CNS的机制及其在CNS内的行为。成年免疫缺陷（裸鼠和严重联合免疫缺陷小鼠）和对照小鼠经外周感染表达绿色荧光蛋白报告基因的重组小鼠CMV。对照小鼠能有效清除急性外周感染，且对CMV侵入大脑具有抵抗力。相比之下，免疫缺陷小鼠的大脑在接种后至少21天才被病毒感染。接种后，在循环白细胞（MAC-3/CD45(+)）和脑内白细胞中发现了CMV，提示这些细胞可能是CMV进入CNS的来源。在许多不同类型的细胞中观察到CNS感染，包括神经元、神经胶质细胞、脑膜、室管膜细胞和脑血管细胞。感染灶在局部逐渐扩展至相邻细胞，导致脑膜炎、脉络膜炎、脑炎、血管炎和坏死；未发现CMV轴突运输的确切证据。CMV在每个大脑中的区域分布都是独特的，由随机分布的单侧病灶组成。通过检测CMV是否通过非特异性血管破坏进入大脑，向血管内注射示踪分子发现，脑内有CMV的小鼠血脑屏障未出现明显破坏。结果表明宿主适应性免疫（尤其是T细胞）在控制CMV进入和传播至大脑方面具有重要作用，这与病毒可能由穿过血脑屏障的循环单核细胞带入大脑的观点一致。
