Placental trophoblast infection and TLR mediated response to congenital CMV

描述（由申请人提供）：开发针对先天性巨细胞病毒（CMV）的有效干预策略是一项主要的公共卫生优先事项。然而，候选巨细胞病毒疫苗策略在临床前动物模型中未能完全预防先天性感染，有效的疫苗仍然是一个难以实现的目标。巨细胞病毒经胎盘感染的致病性尚不明确，更好的理解可能为开发新的干预措施或疫苗策略提供新的见解。在本文中，我们将研究胎盘感染的两个关键方面：(1)toll样受体（TLR）介导的胎盘对巨细胞病毒的先天免疫反应；(2)病毒趋向性和胎盘感染。胎盘滋养层细胞表达的TLRs介导的炎性先天免疫反应可能是控制细菌和病毒侵袭胎盘先天性感染的重要方面。已知CMV可被多个TLR识别，但胎盘TLR介导的对CMV的反应尚不清楚CMV可能绕过胎盘先天免疫并感染子宫内胎儿的机制。这是我们的假设，成功的先天性感染是依赖于巨细胞病毒的能力

DESCRIPTION (provided by applicant): Development of an effective intervention strategy against congenital cytomegalovirus (CMV) is a major public health priority. However, candidate CMV vaccines strategies have been unsuccessful in completely preventing congenital infection in a pre-clinical animal model and an effective vaccine remains an elusive goal. The pathogenicity of CMV transplacental infection is poorly defined and a better understanding may provide fresh insight for the development of a novel intervention or vaccine strategy. In this proposal, we will examine two key aspects of placental infection: (1) Toll-like receptor (TLR) mediated innate immune response of the placenta to CMV; (2) Viral tropism and placental infection. The inflammatory innate immune response mediated via TLRs expressed on key placental cells (trophoblasts) is potentially an important aspect of controlling placental invasion congenital infection by both bacteria and viruses. CMV is known to be recognized by multiple TLRs but the placental TLR mediated response to CMV is poorly defined as is the mechanism by which CMV potentially circumvents the placental innate immunity and infects the fetus in utero. It is our hypothesis that successful congenital infection is reliant upon the ability of CMV to efficiently enter and usurp TLR expressing trophoblast cells, an important component of the placental barrier and placental innate immunity. Potentially, the newly identified endocytic pathway of viral cell entry could be an important factor in the invasion of the placenta and infection of epithelial trophoblasts. We propose to determine the significance of the TLR mediated innate immune response of the placenta to CMV infection in the only small animal model (guinea pig) for congenital CMV. Additionally, using the same animal model, we will define important tropism genes that potentially enable the virus to establish infectious foci in th placenta and subsequently infect the fetus in utero. These studies will employ conventional histopathological and immunohistochemical approaches as well as novel techniques including the use of bioluminescence imaging of viral dissemination in the animal model.