Host Pathways that Enable /Salmonella/ Replication Within Hemophagocytic Macropha

描述(申请人提供)：许多对人类健康重要的细菌病原体生活在白细胞内，从而逃避免疫系统。肠沙门氏菌是一种革兰氏阴性细菌，包括人类伤寒的病原体，存在于一种名为巨噬细胞的白细胞中。在小鼠体内，鼠伤寒沙门氏菌亚种(沙门氏菌)在吞噬红细胞、血小板、白细胞及其前体细胞的吞噬血细胞的巨噬细胞(HM、S)内居住和复制。我们的长期目标是确定沙门氏菌和HM？S如何相互作用导致疾病。感染沙门氏菌的小鼠是一种在野外遇到的自然宿主-病原体模型系统。沙门氏菌会引起小鼠的急性感染，通常会转化为慢性感染，其病程类似于伤寒。细菌在脾、肝和排出肠道的淋巴结处定居。我们在沙门氏菌感染的小鼠的脾、肝和骨髓中发现了HM？S，并在肝脏中发现了HM？S，直到感染后8周才确定为持续感染。在初步研究中，我们建立了一种流式细胞术来鉴定和分离S和其他类型的细胞。这一新的方法学以及已有的方法使我们能够对S先生在疾病中的作用进行新的探索。目前建议的目标是确定HM？S内使这些细胞允许沙门氏菌复制所需的调控途径。完成体内目标可能用于开发调节吞噬血细胞并影响感染和非感染环境中的炎症过程的治疗方法。 公共卫生相关性：这项提议的工作有可能定义新的和重要的宿主-病原体相互作用机制，不仅对于沙门氏菌，而且通过对引发HM的其他微生物的推断？堆积，包括结核分枝杆菌、利什曼原虫和组织胞浆菌。这项拟议研究的长期意义在于，它有可能确定巨噬细胞信号通路作为感染和非感染性疾病的新治疗靶点，HM？S在这些疾病中积累。

DESCRIPTION (provided by applicant): Many bacterial pathogens important to human health evade the immune system by living within white blood cells. Salmonella enterica, a species of gram-negative bacteria that includes the causative agent of human typhoid fever, resides within a class of white blood cells called macrophages. We have demonstrated that in mice, S. enterica subspecies Typhimurium (Salmonella) resides and replicates within hemophagocytic macrophages (HM?s), which are macrophages that have engulfed erythrocytes, platelets, leukocytes and their precursor cells. Our long-term goal is to determine how Salmonella and HM?s interact to cause disease. Mice infected with Salmonella are a natural host-pathogen model system encountered in the wild. Salmonella causes an acute infection in mice that typically resolves into a chronic infection, and the disease course resembles that of typhoid fever. The bacteria colonize the spleen, liver, and the lymph nodes that drain the intestine. We demonstrated the presence of HM?s within the spleen, liver and bone marrow of Salmonella - infected mice and identified HM?s containing Salmonella as late as eight weeks post-infection in the liver, when persistent infection has been established. In Preliminary Studies we developed a flow cytometric assay to identify and separate HM?s from other cell types. This novel methodology along with established approaches enables new exploration of the role of HM?s in disease. The objective of the current proposal is to identify regulatory pathways within HM?s needed to make these cells permissive for Salmonella replication. Completion of the Aims within has potential use in the development of treatments that modulate hemophagocytosis and influence the course of inflammation in infectious and non-infectious circumstances. PUBLIC HEALTH RELEVANCE: The work proposed within has the potential to define new and important mechanisms of host-pathogen interactions not only for Salmonella but by inference for other microbes that trigger HM? accumulation, including Mycobacterium tuberculosis, Leishmania species, and Histoplasma capsulatum. The long-term significance of the proposed research is its potential to identify macrophage signaling pathways as novel therapeutic targets for infectious and non-infectious diseases in which HM?s accumulate.