Molecular Mechanisms of Salmonella typhi Pathogenicity

项目负责人/主要研究者（最后一名、第一名、中间名）：GALAN，JORGE E 1 R 01 AI 070949 - 01 A2 伤寒沙门氏菌（S.伤寒（Typhi）是人类伤寒的原因，仍然是一个非常重要的健康问题。据估计，每年有1600万例伤寒病例，导致60万人死亡。与其他肠道沙门氏菌血清型不同，它可以感染各种宿主，沙门氏菌。伤寒是人类独有的病原体。这些细菌的宿主适应性和独特致病性的分子基础尚不清楚。然而，人们认为，基因组降解和新的遗传信息的获得相结合，赋予了S。伤寒具有独特的致病特性。不同S.伤寒分离株提供了独特的洞察其致病性的潜在决定因素。我们实验室最近的工作集中在一个“致病性胰岛”，这是唯一的S。伤寒这种胰岛编码我们命名为“伤寒毒素”的新毒素。该毒素由两个活性亚基组成，CdtB，细胞致死性扩张毒素（CDT）的活性亚基的同系物，和pltA，百日咳毒素的活性亚基的同系物。我们发现，这种毒素的表达只发生在S。伤寒已到达宿主细胞内的特定细胞内区室。我们实验室最近的工作还确定了一种以前未知功能的调节蛋白STy 044 g，它特异性地控制这种毒素的细胞内表达。我们已经发现，STY 044 B，我们命名为lgeR（细胞内基因表达调节因子），通过直接结合毒素启动子发挥其作为阻遏物的功能。我们还发现igeR在S.鼠伤寒沙门氏菌导致其小鼠毒力急剧下降。因此，我们相信，lgeR调节子的表征及其作用机制将提供一个独特的洞察这种ver/难以捉摸的细菌病原体的细胞内生物学，以及提供一般的细胞内病原体的生物学信息。lt是 因此，本项目的目的是定义lgeR调节子，研究其作用模式，并使用各种体外测定和新型感染动物模型来检查其对毒力的贡献。

Program Director/Principal Investigator (Last, First, Middle):GALAN, JORGE E 1 R01 AI 070949 - 01 A2 Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. lt is estimated that there are 16,000,000 cases of typhoid fever every year, resulting in 600,000 deaths. Unlike other Salmonella enterica serovars, which can infect a variety of hosts, S. Typhi is an exclusive human pathogen. The molecular bases for the host adaptation and unique pathogenicity of these bacteria are not known. However, it is believed that a combination of genome degradation and acquisition of new genetic information has conferred on S. typhiits unique pathogenic properties. The availability of the nucleotide sequence of different S. typhiisolates has provided unique insight into its potential determinants of pathogenicity. Recent work in our laboratory has focused on a "pathogenicity islet" that is unique to S. Typhi. This islet encodes novel toxin that we have named "typhoid toxin". Thisioxin is composed of two active subunits, CdtB, a homolog the active subunit of the Cytolethal Distending Toxin (CDT), and pltA, a homolog of the active subunit of Pertussis toxin. We have found that the expression of this ioxin occurs exclusively when S. Typhi has reached a specific intracellular compartment within host cells. Recent work in our laboratory has also identified a regulatory protein of previously unknown function, STy044g, which specifically controls the intracellular expression of this toxin. We have found that STY044B, which we have named lgeR (for intracellular gene expression regulator), exerts its function as a repressor by binding directly to the toxin promoter. We have also found that constitutive expression of igeR in S. Typhimurium resulted in a drastic reduction in its mouse virulence. We therefore believe that the characterization of the lgeR regulon and its mechanism of action would provide a unique insight into the intracellular biology of this ver/ elusive bacterial pathogen, as well as provide information into the biology of intracellular pathogens in general. lt is therefore the purpose of this project to define the lgeR regulon, to investigate its mode of action and to examine its contribution to virulence using a variety of in-vitro assays and a novel animal model of infection.