Host Pathways that Enable /Salmonella/ Replication Within Hemophagocytic Macropha

描述（由申请人提供）：许多对人类健康很重要的细菌病原体通过生活在白色血细胞中来逃避免疫系统。肠道沙门氏菌是一种革兰氏阴性细菌，包括人类伤寒的病原体，存在于一类称为巨噬细胞的白色血细胞中。我们已经证明，在小鼠中，S。肠道亚种鼠伤寒沙门氏菌（沙门氏菌）在噬血细胞巨噬细胞（HM？s），其是吞噬红细胞、血小板、白细胞及其前体细胞的巨噬细胞。我们的长期目标是确定沙门氏菌和HM？相互作用导致疾病。感染沙门氏菌的小鼠是在野外遇到的天然宿主-病原体模型系统。沙门氏菌引起小鼠急性感染，通常会演变为慢性感染，病程类似于伤寒。这种细菌在脾脏、肝脏和排出肠道的淋巴结中定植。我们证明了HM的存在在沙门氏菌感染的小鼠的脾脏、肝脏和骨髓中发现了HM？s含有沙门氏菌最迟在肝脏感染后8周，当持续感染已经建立。在初步研究中，我们开发了一种流式细胞仪检测，以确定和分离HM？来自其他细胞类型。这种新的方法沿着与既定的方法，使新的探索HM的作用？s在疾病中。目前的建议的目的是确定HM？使这些细胞允许沙门氏菌复制。完成本研究的目的，可用于开发在感染和非感染情况下调节噬血细胞作用并影响炎症过程的治疗方法。 公共卫生相关性：内提出的工作有可能定义新的和重要的宿主-病原体相互作用的机制，不仅为沙门氏菌，但通过推断其他微生物，触发HM？蓄积，包括结核分枝杆菌、利什曼原虫属和荚膜组织胞浆菌。拟议的研究的长期意义是它的潜力，以确定巨噬细胞信号通路作为新的治疗目标的感染性和非感染性疾病，其中HM？S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.