van den Pol Anthony N, Reuter Jon D, Santarelli Justin G
Departments of Neurosurgery. Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Virol. 2002 Sep;76(17):8842-54. doi: 10.1128/jvi.76.17.8842-8854.2002.
Cytomegalovirus (CMV) has been suggested as the most prevalent infectious agent causing neurological dysfunction in the developing brain; in contrast, CMV infections are rare in the adult brain. One explanation generally given for the developmental susceptibility to the virus is that the developing immune system is too immature to protect the central nervous system from viral infection, but as the immune system develops it can protect the brain. We suggest an alternate view: that developing brain cells are inherently more susceptible to CMV infection, independent of the immune system. We used a recombinant mouse CMV that leads to green fluorescent protein expression in infected cells. Control experiments demonstrated a high correlation between the number of cells detected with the viral GFP reporter gene and with immunocytochemical detection of the virus. After intracerebral inoculation, the number of CMV-infected cells in neonatal brains was many times greater than in mature control or mature immunodepressed SCID mice, and the mortality rate of neonates was substantially greater than SCID or control adults. Parallel experiments with live brain slices inoculated in vitro, done in the absence of the systemic immune system, generated similar data, with immature hippocampus, hypothalamus, cortex, striatum, and cerebellum showing substantially greater numbers of infected cells (100-fold) than found in adult slices in these same regions. Interestingly, in the cerebellar cortex, CMV-infected cells were more prevalent in the postmitotic Purkinje cell layer than in the mitotic granule cell layer, suggesting a selective infection of some cell types not dependent on cell division. Together, these data support the view that CMV has an intrinsic preference for infection of developing brain cells, independent, but not mutually exclusive, of the developmental status of the systemic immune system in controlling CMV infection.
巨细胞病毒（CMV）被认为是导致发育中大脑神经功能障碍的最常见感染因子；相比之下，CMV感染在成人大脑中很少见。对于这种病毒在发育阶段易感性的一种普遍解释是，发育中的免疫系统尚未成熟，无法保护中枢神经系统免受病毒感染，但随着免疫系统的发育，它可以保护大脑。我们提出另一种观点：发育中的脑细胞本身更容易受到CMV感染，这与免疫系统无关。我们使用了一种重组小鼠CMV，它能使感染细胞表达绿色荧光蛋白。对照实验表明，用病毒GFP报告基因检测到的细胞数量与病毒免疫细胞化学检测结果之间具有高度相关性。脑内接种后，新生大脑中被CMV感染的细胞数量比成熟对照或成熟免疫抑制的SCID小鼠多很多倍，新生小鼠的死亡率也明显高于SCID或对照成年小鼠。在没有全身免疫系统的情况下，对体外接种的活脑切片进行的平行实验得出了类似的数据，未成熟的海马体、下丘脑、皮层、纹状体和小脑显示出的感染细胞数量（高出100倍）比这些相同区域的成年切片中发现的要多得多。有趣的是，在小脑皮层中，被CMV感染的细胞在有丝分裂后的浦肯野细胞层中比在有丝分裂的颗粒细胞层中更普遍，这表明某些细胞类型存在选择性感染，且不依赖于细胞分裂。总之，这些数据支持这样一种观点，即CMV对发育中脑细胞的感染具有内在偏好，这与全身免疫系统在控制CMV感染中的发育状态无关，但并非相互排斥。
