MCMV Infection of the Developing CNS: Neuroinvasion and Immune Control

描述（由申请人提供）：先天性人巨细胞病毒（HCMV）感染是儿童神经损伤的重要原因，也是美国非家族性听力损失的主要原因。由于缺乏合适的中枢神经系统（CNS）感染模型，对这种感染的发病机制知之甚少。我们已经开发了一种先天性HCMV感染的小鼠模型，该模型重现了先天性HCMV感染中描述的许多组织病理学和神经发育异常，包括存活小鼠的听力损失。与早期模型相反，外周注射鼠CMV的新生小鼠发生病毒血症，随后发生脑炎。由于新生小鼠在神经发育和免疫学上与妊娠晚期的人类胎儿相当，因此该模型也使我们能够研究发育中动物中这种病毒感染的解决方案。在这个建议中，我们将研究这些动物的CNS感染的各个方面，包括神经侵袭的机制，先天免疫应答在清除CNS病毒中的作用，以及先天免疫和适应性免疫应答在清除CNS病毒中的相互作用。最后，将研究先天免疫和适应性免疫在新生儿感染的成年小鼠中持续CNS感染中的作用。我们预计，CMV感染的发病机制的参数，在发展中的中枢神经系统将确定从这些研究。此外，我们认为这些发现可以直接转化为更有针对性的人类研究，从而可能导致预防和治疗这种重要感染的新方法。 公共卫生相关性：发育中的胎儿中的人巨细胞病毒感染是婴儿和儿童脑部疾病的主要原因。目前还没有针对这种从母亲传播给胎儿的感染的疫苗或治疗方法。该项目将利用一种高度相关的小鼠病毒和这种疾病的小鼠模型来了解这种感染导致大脑感染的特征以及限制病毒生长和损害发育中大脑的免疫反应。

DESCRIPTION (provided by applicant): Congenital human cytomegalovirus (HCMV) infection represents an important cause of neurological damage in children and is the leading cause of non-familial hearing loss in the US. Little is understood about the pathogenesis of this infection because suitable models of central nervous system (CNS) infection are lacking. We have developed a murine model of congenital HCMV infection which recapitulates many of the histopathological and neurodevelopmental abnormalities described in congenital HCMV infections, including hearing loss in surviving mice. In contrast to earlier models, newborn mice injected peripherally with murine CMV develop viremia and subsequently, encephalitis. Because newborn mice are neurodevelopmentally and immunologically equivalent to late 2nd trimester human fetuses, this model has also enabled us to study resolution of this virus infection in a developing animal. In this proposal we will study aspects of the CNS infection in these animals including mechanisms of neuroinvasion, the contribution of innate immune responses in clearance of the virus from the CNS, and the interplay between innate immunity and adaptive immune responses in clearance of virus from the CNS. Lastly, the contribution of both innate and adaptive immunity in persistent CNS infection in adult mice infected as newborns will be studied. We anticipate that parameters of the pathogenesis of CMV infection in the developing CNS will be identified from these studies. Furthermore, we believe that these findings can be translated directly into more focused studies in humans that could lead to new approaches for prevention and treatment of this important infection. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus infection in the developing fetus is a major cause of brain disease in infants and children. Currently no vaccines or treatment exist for this infection that is transmitted from the mother to the fetus. This project will utilize a highly related mouse virus and a mouse model of this disease to understand the characteristics of this infection that result in brain infection and the immune responses that limit virus growth and damage to the developing brain.