SALMONELLA VIRULENCE FACTORS--HOST RESPONSE TO INFECTION

沙门氏菌是引起肠炎和肠炎的主要肠道病原体 系统性疾病。本单位的总体目标是利用 资源的计划项目在互动的方式来阐明 沙门氏菌在肠道中致病的关键方面以及 在全身组织中。沙门氏菌是一个很好的模型， 在肠道中的侵袭性肠发病机制以及在 全身组织沙门氏菌是一个很好的模型， 肠道病原体，因为有机体是服从详细的分子 遗传分析具体目标1是鉴定S.鼠伤寒杆菌基因， 对于感染人肠上皮细胞是重要的， 刺激促炎上皮细胞反应。这种方法 将利用Kagnoff博士实验室在上皮细胞方面的专业知识 对粘膜感染作出反应的信号。中的特定突变 沙门氏菌控制附着侵入和细胞内生长的基因 将测试对培养的人类上皮细胞的影响， 在SCID小鼠中使用人肠异种移植物进行体内检查。具体 目的二是分离S.鼠伤寒沙门氏菌和测定 毒力表型这个建议直接来源于工作 这表明，替代西格玛因子西格玛（RpoS）是一个突出的 沙门氏菌感染宿主细胞过程中的调节元件，包括 肠上皮细胞rpoS调控基因将通过以下方法鉴定： 分子遗传学方法和毒力也将在小鼠中进行测试 如在人类肠道感染的模型中。具体目标3是确定 多形核白细胞在a）天然抗口服 不同O抗原类型的沙门氏菌感染，B）保护小鼠 具有缺陷的巨噬细胞功能（突变的Nramp 1等位基因）， 沙门氏菌感染;和c）获得性免疫（抗体介导）， 沙门氏菌。这一目标将补充上皮细胞的能力， 细胞启动促炎宿主反应，并将重点放在 关键的宿主防御，限制感染的传播，从 肠至全身部位。

Salmonella are prominent intestinal pathogens that cause both enteritis and systematic disease. The overall goal of this unit is to utilize the resources of the Program Project in an interactive approach to elucidate key aspects of Salmonella pathogenesis in the intestinal tract as well as in systemic tissues. Salmonella represents an excellent model for an invasive intestinal pathogenesis in the intestinal tract as well as in systemic tissues. Salmonella represents an excellent model for an invasive intestinal pathogen since the organism is amenable to detailed molecular genetic analysis. Specific Aim 1 is to identify S. typhimurium genes that are important for infection of human intestinal epithelial cells and stimulation of pro-inflammatory epithelial cell responses. This approach will utilize the expertise of Dr. Kagnoff's laboratory in epithelial cell signaling in response to mucosal infections. Specific mutations in Salmonella genes governing attachment invasion and intracellular growth will be tested for effects on human epithelial cells in culture and examined in vivo using human intestinal xenografts in SCID mice. Specific Aim 2 is to isolate rpoS-regulated genes in S. typhimurium and determine their virulence phenotypes. This proposal is directly derived from work showing that the alternative sigma factor sigmas (RpoS) is a prominent regulatory element during Salmonella infection of host cells, including intestinal epithelial cells. rpoS-regulated genes will be identified by a molecular genetic approach, and virulence will be tested in mice as well as in models of human intestinal infection. Specific Aim 3 is to determine the roles of polymorphonuclear leukocytes in a) natural resistance to oral infections by Salmonella of different O antigen types, b) protecting mice that have defective macrophage function (a mutant Nramp 1 allele) from Salmonella infections; and c) acquired immunity (antibody mediated) to Salmonella. This aim will complement work on the ability of epithelial cells to initiate the pro-inflammatory host response, and will focus on crucial host defenses that limit the spread of infection from the intestine to systemic sites.