Persistent Systemic Infection of Mice by Salmonella Enterica

描述（由申请人提供）：相关性-慢性细菌感染在世界范围内引起显著的发病率和死亡率。世界卫生组织估计，每年有170万人死于结核分枝杆菌感染，这种细菌可以在健康的宿主体内潜伏多年。肠道沙门氏菌血清型也可引起慢性无症状感染，其中表面健康的宿主间歇性地排出病原体。这种情况为每年约有1700万本国人感染急性伤寒创造了条件。我们的计划是了解慢性感染是如何在分子和细胞水平上建立和维持的。为了实现这一目标，我们将使用持续肠道沙门氏菌感染的小鼠模型。这个模型是一个很好的模型，因为它检验了遗传易感动物的自然感染。我们提出的工作的一个主要焦点是Res（胶囊合成调节）信号通路，我们发现它有助于在我们的小鼠模型中建立持续感染。利用细菌突变体和DNA微阵列，我们鉴定了127个res激活基因，包括促进或限制沙门氏菌在体内定植的基因。这一发现与我们的假设一致，即细菌定植过多或过少都可以预防慢性疾病的发生；过少的定植可能允许细菌清除，很少或没有急性感染的迹象，而过多的定植可能刺激免疫系统有效地消灭细菌。我们将从探索两个关键的res激活基因的作用开始，我们已经证明它们对定植有相反的影响。我们也有数据表明，尚未表征的rcs调控成员可以提高沙门氏菌在干扰素刺激的巨噬细胞中的存活率，我们将鉴定这些基因。干扰素刺激的巨噬细胞与慢性感染有关，因为它们而不是静止的巨噬细胞，在重新播种时可能会遇到沙门氏菌。此外，我们将继续研究我们最近的发现，即宿主干扰素-g信号通路对于沙门氏菌在持续感染期间复制的细胞生态位的创建很重要，但在急性感染期间没有观察到。

DESCRIPTION (provided by applicant): Relevance - Chronic bacterial infections cause significant morbidity and mortality worldwide. The World Health Organization estimates that 1.7 million people per year die from Mycobacterium tuberculosis infections, which can lie dormant in a healthy host for years. Salmonella enterics serotypes can also cause chronic asymptomatic infections in which an apparently healthy host sheds the pathogen intermittently. This situation sets the stage for acute typhoid fever in approximately 17 million naTve hosts each year. Our plan is to understand how, at the molecular and cellular levels, chronic infections are established and maintained. To accomplish this goal we will use a mouse model of persistent Salmonella enterica infection. This model is an excellent one because it examines a natural infection in a genetically tractable animal. A major focus of our proposed work is the Res (Regulation of capsule synthesis) signaling pathway, which we found contributes to the establishment of persistent infection in our mouse model. Using bacterial mutants and DNA microarrays, we have identified 127 Res-activated genes, including genes that either promote or limit in vivo colonization by Salmonella. This finding is consistent with our hypothesis that the establishment of chronic disease is prevented by both too much and too little bacterial colonization; too little colonization may allow for bacterial clearance with few or no signs of acute infection, whereas too much colonization may stimulate the immune system to efficiently eliminate the bacteria. We will begin by exploring the roles of two critical Res-activated genes that we have shown oppositely affect colonization. We also have data indicating that as-yet-uncharacterized members of the Rcs-regulon enhance Salmonella survival in interferon-g stimulated macrophages, and we will identify these genes. Interferon-g stimulated macrophages are relevant to chronic infection because they, rather than resting macrophages, are likely encountered by Salmonella upon re-seeding. In addition, we will pursue our recent findings that the host interferon-g signaling pathway is important for the creation of a cellular niche in which Salmonella replicates during persistent infection but which has not been observed during acute infection.