Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS Pathog. 2013 Mar;9(3):e1003200. doi: 10.1371/journal.ppat.1003200. Epub 2013 Mar 7.
Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.
人类巨细胞病毒（HCMV）感染发育中的胎儿是婴儿和儿童中枢神经系统疾病的主要原因；然而，与这种宫内感染相关的疾病机制仍知之甚少。利用 HCMV 感染发育中的中枢神经系统的小鼠模型，我们已经表明，新生小鼠外周接种鼠巨细胞病毒（MCMV）会导致中枢神经系统感染和发育异常，这些异常重现了人类感染的关键特征。在该模型中，动物表现出颗粒神经元前体细胞（GNPC）增殖减少和小脑皮质形态发生改变。尽管中枢神经系统感染导致以广泛散布的病毒感染细胞与单核细胞浸润为特征的非坏死性脑炎，但小脑皮质发育缺陷是对称和全局的。这些发现表明，MCMV 感染引起的炎症可能是中枢神经系统发育缺陷的原因。我们通过用糖皮质激素调节感染小鼠的宿主炎症反应来研究炎症反应对异常小脑发育的贡献。用糖皮质激素治疗感染动物可减少中枢神经系统单核细胞的激活和中枢神经系统中炎症细胞因子（TNF-α、IFN-β 和 IFNγ）的表达，而对中枢神经系统病毒复制的影响最小。糖皮质激素治疗还限制了形态异常，并使小脑内发育调节基因的表达正常化。重要的是，在 MCMV 感染的小鼠中，糖皮质激素治疗后 GNPC 增殖缺陷得到了正常化。我们的研究结果表明，宿主对 MCMV 感染的炎症反应导致 MCMV 感染小鼠中枢神经系统发育缺陷，并表明类似的疾病机制可能是导致宫内感染 HCMV 的人类婴儿中枢神经系统发育异常的原因。
