Macrophages, Granulomas, and Bacterial Persistence

摘要 肠沙门氏菌亚种鼠伤寒沙门氏菌是小鼠的一种天然病原体，它建立了持久的、系统性的 感染。沙门氏菌通常存在于专业吞噬细胞内，通常是巨噬细胞，这是至关重要的。 用于慢性感染的发展。然而，目前尚不清楚沙门氏菌如何在一种细胞类型中存活 进化来消灭病原体的生物。我们的实验室已经证明，在持续的小鼠感染期间，S. 鼠伤寒沙门氏菌可以存在于吞噬血细胞的巨噬细胞内。噬血巨噬细胞(HMФS) 以摄取造血系的活细胞为特征，临床上与 人类伤寒。我们还观察到，在感染后三周，激活的巨噬细胞，以及 可能是HMФS，融合成肉芽肿，似乎保护细菌免受宿主免疫 系统，潜在地建立了一个细菌可以长期生存的场所。这项提议的目标是 为了确定鼠伤寒沙门氏菌如何利用巨噬细胞，包括HMФS和肉芽肿内的巨噬细胞， 在急性和慢性感染期间抵抗宿主的防御。我们正在为HMФS和肉芽肿建模 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 HMФ中的组织S和肉芽肿：1)鼠伤寒沙门氏菌是如何从巨噬细胞获取铁的？和 2)鼠伤寒沙门氏菌是如何在肉芽肿中存活的？肉芽肿是如何形成、获得和维持的 沙门氏菌等细菌仍然是一个知之甚少的领域，可能能够成为治疗的靶点。

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.