Persistent Systemic Infection of Mice by Salmonella Enterica

描述(由申请人提供)：相关性-慢性细菌感染在全球范围内导致严重的发病率和死亡率。世界卫生组织估计，每年有170万人死于结核分枝杆菌感染，这种细菌可能会在健康的宿主中潜伏多年。肠道沙门氏菌的血清型也可以引起慢性无症状感染，在这种感染中，表面上健康的宿主间歇性地排出病原体。这种情况为每年约1700万NATve宿主中的急性伤寒奠定了基础。我们的计划是在分子和细胞水平上了解慢性感染是如何建立和维持的。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，因为它检查了一种遗传上易驯服的动物的自然感染。我们建议的工作的一个主要焦点是Res(调节包膜合成)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，我们已经确定了127个RES激活的基因，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，即细菌定植过多和过少都能防止慢性病的建立；定植太少可能会导致细菌清除，几乎没有急性感染的迹象，而定植太多可能会刺激免疫系统有效地清除细菌。我们将从探索两个关键的Res激活基因的作用开始，我们已经证明了这两个基因相反地影响着殖民。我们也有数据表明，RCS-调节子的未知成员增强了沙门氏菌在干扰素-g刺激的巨噬细胞中的存活，我们将鉴定这些基因。干扰素-g刺激的巨噬细胞与慢性感染有关，因为沙门氏菌在重新播种时可能会遇到它们，而不是静止的巨噬细胞。此外，我们将继续我们最近的发现，宿主干扰素-g信号通路对于创造沙门氏菌在持续感染期间复制的细胞生态位是重要的，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.