Seleme Maria C, Kosmac Kate, Jonjic Stipan, Britt William J
Department of Pediatrics Infectious Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Virol. 2017 Mar 29;91(8). doi: 10.1128/JVI.01983-16. Print 2017 Apr 15.
Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-α)-neutralizing antibodies decreased the frequency of CD45 Ly6C CD11b CCR2 activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMV-infected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-α is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain. Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-α plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-α normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected with HCMV.
先天性人类巨细胞病毒（HCMV）感染是婴幼儿神经发育异常和长期神经后遗症的重要原因。发育中的大脑中的常驻细胞群被认为更容易受到病毒诱导的细胞病变影响，这一途径被认为与宫内HCMV感染后的临床结果有关。然而，最近在发育中大脑感染的新生小鼠模型中的研究结果表明，导致单核细胞激活和募集的促炎介质水平升高可能是神经发育异常的基础。在本研究中，我们证明用肿瘤坏死因子α（TNF-α）中和抗体治疗可降低小鼠巨细胞病毒感染小鼠血液和大脑中CD45 Ly6C CD11b CCR2活化髓样单核细胞（MMCs）的频率以及促炎细胞因子的水平。这种治疗还使感染小鼠的神经发育正常化，而不会显著影响病毒复制水平。这些结果表明，TNF-α是与发育中大脑感染小鼠巨细胞病毒后神经发育改变相关的炎症反应的主要成分，并且外周血髓样单核细胞的一个亚群代表了这种发育中大脑病毒诱导的炎症性疾病模型中的关键效应细胞群。先天性人类巨细胞病毒（HCMV）感染是发育中的人类胎儿最常见的病毒感染，可导致神经发育后遗症。导致受感染婴儿神经发育缺陷的疾病机制仍不明确，但推测的途径包括神经元祖细胞的丧失、大脑发育中血管系统的损伤以及细胞定位的改变。直接的病毒介导的细胞病变效应无法解释大多数受感染婴儿的脑损伤表型。使用一个概括人类婴儿大脑感染特征的小鼠模型，我们已经表明TNF-α在脑炎症中起关键作用，包括炎症单核细胞的募集。TNF-α的中和使感染小鼠的神经发育异常正常化，提供了病毒诱导的炎症是发育中大脑疾病的主要成分的证据。这些结果表明，限制与感染相关炎症的干预措施可能会改善感染HCMV的婴儿的神经学结局。
