FRAGILE ANIMAL MODELS OF HUMAN DISEASE

项目1：严重联合免疫缺陷和免疫活性小鼠的使用 口腔李氏杆菌病（及中枢神经系统疾病）的发病机制分析 我们建议使用严重联合免疫缺陷（scid）， 免疫活性（imcomp）小鼠，常规饲养（CNV）或 无肠道微生物植物群（GF，无菌）作为模型来分析 致病机理或口腔感染。单核细胞增多症和宿主反应 肠道粘膜的挑战。L.单核细胞增多症是一种机会主义， 有时是致命的，是人类的病原体， 食用动物我们开发了第一个实验室动物模型， 中枢神经系统（CNS）-口腔感染后的绦虫病。口服 用“野生型”L.单核细胞增多症导致 CNS感染和症状-经典的“循环疾病”和死亡 在14-21天内。 我们计划使用“野生型”强毒L。单核细胞增多症和四种毒力- 单核细胞增生李斯特菌因子阴性（“敲除”）菌株以探测 通过肠粘膜途径的发病机制以及 宿主的粘膜免疫系统的成分可以起到预防，遏制， 解决肠道粘膜感染我们相信我们的发现 来理解和免疫肠道粘膜感染。我们认为 我们的发现可能有助于理解免疫与肠道 许多兼性细胞内细菌病原体引起的粘膜感染。 目的：1）分析口腔/肠道粘膜L。单核细胞增多症可以 移位肠道，传播和通过血脑屏障; 2） 评估宿主粘膜免疫系统的哪些成分可能起作用， 预防和限制感染; 3）确定是“先天”还是“自然” 免疫机制可能在限制肠道感染方面起作用 粘膜途径; 4）使用L.单核细胞增生性粘膜感染作为模型， 评价分泌型伊加Ab是否能有效地遏制感染 粘膜上皮被细菌性细胞内病原体破坏。

Project 1: Use of Severe Combined Immunodeficient and Immunocompetent Mice to Analyze the Pathogenesis of Oral Listeriosis (and CNS-Disease) We propose to use Severe Combined Immunodeficient (scid) and Immunocompetent (imcomp) mice, either conventionally reared (CNV) or with no gut microbial flora (GF, germ free) as models to analyze the pathogenesis or oral infection by L. monocytogenes and the host response to such gut mucosal challenge. L. monocytogenes is an opportunistic, sometimes fatal, pathogen of humans and a more common pathogen of domestic food animals. We have developed the first laboratory animal model for Central Nervous System (CNS)-listeriosis following oral infection. Oral infection of CNV scid mice with 'wild-type' L. monocytogenes results in CNS-infection and symptoms--classically 'circling disease' and death within 14-21 days. We plan to use 'wild-type' virulent L. monocytogenes, and four virulence- factor negative ('knock-out') strains of L.monocytogenes to probe the mechanisms of pathogenesis via the gut mucosal route and the role the elements of the host's mucosal immune system may play to prevent, contain, and resolve gut mucosal infections. We believe our finds may be relevant to understanding and immunizing versus gut mucosal infections. We believe our findings may be relevant to understand and immunizing versus gut mucosal infections by many facultative, intracellular bacterial pathogens. We aim to: 1) analyze how oral/gut mucosal L. monocytogenes can translocate the gut, disseminate and transit the blood-brain barrier; 2) evaluate which elements of the host's mucosal immune system may act to prevent and limit infection; 3) determine whether 'innate' or 'natural' immune mechanisms may be effecting at limiting infection by the gut mucosal route; 4) use L. monocytogenes mucosal infections as a model for evaluating whether secretory IgA Abs can effectively contain an infection of the mucosal epithelium by a bacterial intracellular pathogen.