Virulence factors of Salmonella Typhi

描述(申请人提供)：伤寒沙门氏菌(伤寒沙门氏菌)，人类伤寒的起因，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。虽然大多数病例发生在发展中国家，但美国偶尔也会爆发疫情。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还知之甚少。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。我们实验室的工作最近集中在伤寒沙门氏菌所特有的“致病胰岛”上。我们发现染色体的这一区域编码一种细胞致死性膨胀毒素和一种百日咳样毒素。值得注意的是，这些毒素只有在伤寒沙门氏菌到达细胞内位置时才被合成，并通过一种独特的运输机制被输出到细胞外，然后通过新的旁分泌和自分泌途径输送到靶细胞。此外，我们还发现，这些毒素具有共同的独特的分泌机制，可以从细菌细胞质中输出。在这个研究项目中，我们打算描述这种独特的毒素传递途径及其独特的分泌机制。我们还想通过伤寒沙门氏菌的致病机制及其与宿主细胞的相互作用来确定它们对毒力的贡献。这些研究将提供对伤寒沙门氏菌独特而重要的致病机制的洞察，伤寒沙门氏菌是一种令人惊讶的正在研究但非常重要的人类病原体。公共卫生相关性：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。从这项研究中获得的知识应该有助于开发新的治疗和预防策略。

DESCRIPTION (provided by applicant): Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. It is estimated that there are 16,000,000 cases of typhoid fever every year, resulting in 600,000 deaths. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. 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 poorly understood. However, it is believed that a combination of genome degradation and acquisition of new genetic information has conferred on S. Typhi its unique pathogenic properties. Work in our laboratory has recently focused on a "pathogenicity islet" that is unique to S. Typhi. We have discovered that this region of the chromosome encodes a Cytolethal Distending Toxin, and a Pertussis-like toxin. Remarkably, these toxins are only synthesized when S. Typhi reaches an intracellular location and are exported outside the cell by a unique transport mechanism to be subsequently delivered to target cells by novel paracrine and autocrine pathways. Furthermore, we have found that these toxins share a common unique secretion mechanism for export from the bacterial cytoplasm. In this research project, we intend to characterize this unique toxin delivery pathway and their unique secretion mechanism. We also would like to define their contribution to virulence in the context of S. Typhi pathogenesis and its interaction with host cells. These studies will provide insight into unique and important mechanisms of pathogenicity of S. Typhi, a surprisingly under study but very important human pathogen. PUBLIC HEALTH RELEVANCE: Salmonella enterica serovar Typhi (S. typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. It is estimated that there are 16,000,000 cases of typhoid fever every year, resulting in 600,000 deaths. Knowledge gained from this research should help develop novel therapeutic and prevention strategies.