Molecular Mechanisms of Salmonella typhi Pathogenicity

项目总监/首席调查员(最后、第一、中间)：加兰，豪尔赫E-1 R01 AI 070949-01 A2 伤寒沙门氏菌(伤寒沙门氏菌)是导致人类伤寒的原因，它仍然是一个非常严重的健康问题。据估计，每年有1600万伤寒病例，导致60万人死亡。与其他能感染多种宿主的肠道沙门氏菌不同，伤寒沙门氏菌是一种人类独有的病原体。这些细菌的寄主适应和独特致病性的分子基础尚不清楚。然而，人们认为，基因组退化和新遗传信息的获取相结合，赋予了伤寒沙门氏菌独特的致病特性。不同伤寒沙门氏菌核苷酸序列的可获得性为其致病性的潜在决定因素提供了独特的见解。我们实验室最近的工作集中在伤寒沙门氏菌所特有的“致病胰岛”上。这个胰岛编码了一种新的毒素，我们将其命名为伤寒毒素。硫杆菌毒素由两个活性亚基组成，CDtB是细胞致死性膨胀毒素(CDT)活性亚基的同源物，pltA是百日咳毒素活性亚基的同源物。我们发现，当伤寒沙门氏菌到达宿主细胞内的特定细胞内时，这种ioxin的表达仅发生在宿主细胞内。我们实验室最近的工作还发现了一种功能未知的调节蛋白STy044g，它专门控制这种毒素的细胞内表达。我们发现STY044B，我们已经命名为LGER(细胞内基因表达调节因子)，通过直接与毒素启动子结合来发挥其抑制因子的功能。我们还发现，Iger在鼠伤寒沙门氏菌中的结构性表达导致了其小鼠毒力的急剧下降。因此，我们认为，对lger调节子及其作用机制的表征将为这种难以捉摸的细菌病原体的细胞内生物学提供独特的见解，并为一般细胞内病原体的生物学提供信息。就是这样 因此，本项目的目的是定义lger调节子，研究其作用方式，并利用各种体外试验和一种新的动物感染模型来研究其对毒力的贡献。

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.