MCMV Infection of the Developing CNS: Neuroinvasion and Immune Control

描述（由申请人提供）：先天性人类巨细胞病毒（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。我们已经建立了先天性HCMV感染的小鼠模型，该模型概括了先天性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丧失。与早期模型相反，新生小鼠外周注射小鼠巨细胞病毒后出现病毒血症，随后出现脑炎。由于新生小鼠在神经发育和免疫方面与妊娠晚期的人类胎儿相当，因此该模型也使我们能够在发育中的动物中研究这种病毒感染的解决方案。在本研究中，我们将研究这些动物的中枢神经系统感染，包括神经入侵机制、先天免疫反应在清除中枢神经系统病毒中的作用，以及先天免疫和适应性免疫反应在清除中枢神经系统病毒中的相互作用。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持续中枢神经系统感染中的作用。我们预计CMV感染发展中的中枢神经系统的发病机制参数将从这些研究中确定。此外，我们相信这些发现可以直接转化为更有针对性的人类研究，这可能会导致预防和治疗这种重要感染的新方法。

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.