Macrophages, Granulomas, and Bacterial Persistence

总结 肠道沙门氏菌亚种鼠伤寒沙门氏菌是小鼠的天然病原体， 感染沙门氏菌通常存在于专职吞噬细胞内，通常是巨噬细胞，这是至关重要的 发展成慢性感染然而，目前还不清楚沙门氏菌是如何在一种细胞类型中存活的。 它们进化到可以消灭病原体我们的实验室已经证明，在持续的小鼠感染，S。 鼠伤寒沙门氏菌可以存在于噬血细胞的巨噬细胞内。噬血细胞巨噬细胞（HM） 特征在于摄取造血谱系的活细胞，并且临床上与 人类伤寒我们还观察到，感染后三周，活化的巨噬细胞， 可能是HM囊泡，合并成肉芽肿，这些肉芽肿隐藏并似乎保护细菌免受宿主免疫 系统，可能建立一个网站，在那里细菌可以长期生存。这项提案的目的是 确定S.鼠伤寒杆菌利用巨噬细胞，包括肉芽肿内的HM和巨噬细胞， 在急性和慢性感染期间抵抗宿主防御。我们正在模拟HM肉芽肿和肉芽肿 以下两个目标将解决有关细菌如何建立和维持定植的关键问题。 HM肉芽肿和肉芽肿内的组织：1）S。鼠伤寒从巨噬细胞获得铁？和 2)S如何鼠伤寒杆菌能在肉芽肿中存活吗肉芽肿如何形成、获得和维持 诸如沙门氏菌的细菌仍然是一个知之甚少的领域，其可能能够被治疗剂靶向。

Summary Salmonella enterica subspecies Typhimurium is a natural pathogen of mice that establishes persistent, systemic infection. Salmonella generally reside within professional phagocytes, typically macrophages, which is critical for the development of chronic infection. However, it is unclear how Salmonella can survive within a cell-type that evolved to destroy pathogens. Our lab has demonstrated that during persistent murine infections, S. Typhimurium can reside within macrophages that are hemophagocytic. Hemophagocytic macrophages (HMФs) are characterized by the ingestion of viable cells of the hematopoietic lineages, and are clinically associated with human Typhoid fever. We have also observed that by three weeks post-infection, activated macrophages, and possibly HMФs, coalesce into granulomas that harbor and appear to protect bacteria from the host immune system, potentially establishing a site at which the bacteria can survive long-term. The goal of this proposal is to determine how S. Typhimurium exploits macrophages, including HMФs and macrophages within granulomas, to withstand host defenses during acute and chronic infection. We are modeling HMФs and granulomas and the following two aims will address key questions regarding how bacteria establish and maintain colonization of tissues within HMФs and granulomas: 1) How does S. Typhimurium acquire iron from macrophages? and 2) How does S. Typhimurium survive in granulomas? How granulomas form and acquire and maintain bacteria such as Salmonella remains a poorly understood area that may be able to be targeted with therapeutics.