MOLECULAR PATHOGENESIS OF SALMONELLA TYPHIMURIUM

沙门氏菌是肠道侵入性病原体，可引起多种 包括肠胃炎、菌血症和伤寒在内的疾病。 的 这项研究的长期目标是了解，在 在分子水平上，鼠伤寒沙门氏菌 绕过宿主免疫系统导致疾病 了解 发病机制的分子基础， 必须确定这些过程的具体要求， 表征了 我们设计了一个基因系统， 鼠伤寒沙门氏菌基因在某些时候被特异性诱导 在感染期间。 使用这个系统，两个以前没有特征的 在肠道定植期间特异性诱导的基因具有 被识别。 其中一个基因的失活表明， 鼠伤寒沙门氏菌特别需要产品， 有效地定殖在小鼠肠道中。 这个基因并不发挥作用， 在疾病过程的系统性阶段中的作用。 具体 毒力基因产物在宿主中的功能将通过 分析这些基因中定义的突变对 感染过程。 这些毒力基因的调控将是 考察 这将包括识别任何交易 在宿主中诱导这些基因所需的因子，以及 作为引发这种调节的内部宿主信号， 通过对这些操纵子进行详细的遗传分析， 基因融合技术 基因产物的生化分析将 使我们能够进一步确定其在发病机制中的具体作用。 美国沙门氏菌病的发病率在2008年显著增加， 过去十年 事实上，估计每年的治疗费用和 在美国，沙门氏菌感染造成的商业损失为40亿美元。 沙门氏菌感染在艾滋病患者中很常见， 复发性沙门氏菌菌血症是一种确定艾滋病的疾病。 增加 了解疾病的过程将导致更好的方法， 预防和治疗。 这里提出的工作有直接的 对疫苗开发和抗生素药物开发的影响， 应该提供信息，不仅是关于毒力机制的信息， 细菌，而且还主机的功能设计，以防止 细菌感染

The Salmonellae are enteroinvasive pathogens that cause a variety of diseases including gastroenteritis, bacteremia, and typhoid fever. The long-term objectives of this research are to understand, at the molecular level, the mechanisms by which Salmonella typhimurium circumvents the host immune system and causes disease. To understand the molecular basis of pathogenesis, the gene products that are specifically required for those processes must be identified and characterized. We have devised a genetic system that selects for Salmonella typhimurium genes that are specifically induced at some point during the infection. Using this system two previously uncharacterized genes that are specifically induced during intestinal colonization have been identified. Inactivation of one of these genes suggests that its product is specifically required for Salmonella typhimurium to efficiently colonize the mouse intestine. This gene does not play a role in the systemic stages of the disease process. The specific function of the virulence gene products in the host will be addressed by analyzing the effects of defined mutations in these genes on the infection process. The regulation of these virulence genes will be examined. This will include the identification of any trans-acting factors required for the induction of these genes in the host, as well as the internal host signals that elicit this regulation, and will be accomplished through a detailed genetic analysis of these operons using gene fusion technology. Biochemical analysis of the gene products will allow us to further define their specific role in pathogenesis. The incidence of salmonellosis in the US has significantly increased in the last decade. Indeed, the estimated annual cost of treatment and business losses due to Salmonella infections in the US is $4 billion. Salmonella infection is a common occurrence in patients with AIDS, and recurrent Salmonella bacteremia is an AIDS-defining illness. Increased understanding of the disease process will lead to better methods of prevention and treatment. The work proposed here has direct implications for vaccine development and antibiotic drug development and should provide information, not only about virulence mechanisms of the bacteria, but also the functions of the host designed to prevent bacterial infections.