Vertical transmission of Listeria monocytogenes

描述(申请人提供)：胎儿-胎盘感染是妊娠并发症的主要原因，但垂直传播的潜在分子和细胞机制尚不清楚。已知的引起胎盘感染的微生物主要是细胞内的病原体。其中包括单核细胞增多性李斯特氏菌，它很容易进行实验分析。我们建议使用单核细胞增多性乳杆菌作为细胞内病原体的模型，以了解经胎盘传播的机制。我们开发了一种模拟人类疾病的怀孕豚鼠李斯特菌病模型。在人类和豚鼠的胎盘中，只有一层滋养细胞将胎儿和母体的血液循环分开。我们建议描述体内单核细胞增多性李斯特菌和滋养层细胞之间的相互作用，并确定胎盘感染所必需的李斯特菌毒力因子。除了形成物理屏障外，滋养层细胞被认为是对感染的先天免疫反应的一部分。我们建议通过基因芯片分析滋养层细胞对单核细胞增多性李斯特菌感染的基因表达。了解胎盘传播的机制将有助于设计更有效的治疗和预防疾病的手段。 申请者是董事会认证的儿科医生，隶属于加利福尼亚州奥克兰儿童医院感染科。她在儿科科学家发展计划的支持下发起了这个项目，并打算在这个申请的支持下继续她的研究。这项研究将在加州大学伯克利分校的丹尼尔·A·波特诺伊教授的实验室进行，他领导的实验室帮助建立了单核细胞增多性李斯特菌作为宿主-病原体相互作用的模型。这项拟议的研究将提供重要的培训，当申请者成为一名独立的内科科学家时，这将被证明是至关重要的，这是她的长期目标。

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.