SALMONELLA VIRULENCE FACTORS--HOST RESPONSE TO INFECTION

沙门氏菌是引起两种肠炎的主要肠道病原体 和系统性疾病。本单位的总体目标是利用 以互动方式阐明计划项目的资源 沙门氏菌在肠道中致病的关键因素 在全身组织中。沙门氏菌代表着一种优秀的 侵袭性肠道病机在肠道和在 全身组织。沙门氏菌代表着一种极好的侵入性模型 肠道病原体，因为有机体容易受到详细分子的影响 基因分析。具体目标1是鉴定鼠伤寒沙门氏菌的基因 对人类肠道上皮细胞的感染和 刺激促炎上皮细胞反应。这种方法 将利用Kagnoff博士的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。基因中的特定突变 控制附着、侵袭和细胞内生长的沙门氏菌基因 将在培养和培养过程中测试对人类上皮细胞的影响 在SCID小鼠体内使用人异种小肠移植进行检测。特定的 目的2从鼠伤寒沙门氏菌中分离rpos调控基因并确定 它们的毒力表型。这项建议直接来源于工作 表明替代西格玛因子西格玛(Rpos)是一个显著的 沙门氏菌感染宿主细胞的调节元件，包括 肠上皮细胞。受rpos调控的基因将通过 分子遗传学方法，毒力也将在小鼠身上进行测试 就像人类肠道感染的模型一样。具体目标3是确定 中性粒细胞在口腔自然抵抗中的作用 不同O抗原类型的沙门氏菌感染，b)保护小鼠 有缺陷的巨噬细胞功能(突变的Nramp 1等位基因)来自 沙门氏菌感染；以及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能力方面的工作。 启动促炎宿主反应的细胞，并将重点放在 关键的宿主防御，限制感染从 从肠道到全身部位。

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.