Vertical transmission of Listeria monocytogenes

描述（由申请人提供）：胎儿-胎盘感染是妊娠并发症的主要原因，但其垂直传播的潜在分子和细胞机制尚不清楚。已知引起胎胎盘感染的微生物主要是细胞内病原体。其中有单核细胞增生李斯特菌，它非常适合实验分析。我们建议使用单核增生乳杆菌作为细胞内病原体的模型来了解经胎盘传播的机制。我们开发了一种模仿人类疾病的李斯特菌病怀孕豚鼠模型。在人类和豚鼠的胎盘中，单层滋养细胞将胎儿与母体循环分开。我们建议在体内鉴定单核增生乳杆菌和滋养细胞之间的相互作用，并确定胎儿-胎盘感染所必需的李斯特毒力因子。除了形成物理屏障外，滋养细胞被认为是对感染的先天免疫反应的一部分。我们建议用微阵列技术分析滋养细胞对单核增生乳杆菌感染的基因表达。了解经胎盘传播的机制将有助于设计更有效的治疗和疾病预防手段。

DESCRIPTION (provided by applicant): Feto-placental infections represent a major cause for pregnancy complications, yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Organisms known to cause feto-placental infection are predominantly intracellular pathogens. Among those is Listeria monocytogenes, which is highly amenable to experimental analysis. We propose to use L. monocytogenes as a model intracellular pathogen to understand the mechanisms of transplacental transmission. We have developed a pregnant guinea pig model of listeriosis which mimics human disease. A single layer of trophoblasts separates fetal from maternal circulation in the placenta of humans and guinea pigs. We propose to characterize the interaction between L. monocytogenes and trophoblasts in vivo and to identify listerial virulence factors that are necessary for feto-placental infection. In addition to forming a physical barrier trophoblasts are thought to be part of the innate immune response to infection. We propose to analyze gene expression in trophoblasts in response to infection with L. monocytogenes by microarray analysis. Understanding the mechanisms of transplacental transmission will help in designing more effective means of treatment and disease prevention. The applicant is a board certified pediatrician and is affiliated with the Department of Infectious Diseases at Children's Hospital Oakland, CA. She has initiated this project with support from the Pediatric Scientist Development Program and intends to continue her studies with support from this application. The research will be conducted in the laboratory of Prof. Daniel A. Portnoy at UC Berkeley, who heads a laboratory that has been instrumental in establishing L. monocytogenes as a model for host-pathogen interactions. The proposed research will provide important training which will prove crucial for the applicant when she becomes an independent physician scientist, her long-term goal.