Host Pathways that Enable /Salmonella/ Replication Within Hemophagocytic Macropha

描述（由申请人提供）：许多对人类健康重要的细菌病原体通过生活在白细胞内逃避免疫系统。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，它存在于一类被称为巨噬细胞的白细胞中。我们已经证明，在小鼠中，肠炎沙门氏菌亚种鼠伤寒沙门氏菌（沙门氏菌）存在于噬血细胞巨噬细胞(HM？S)，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？S相互作用导致疾病小鼠感染沙门氏菌是在野外遇到的一种自然宿主-病原体模型系统。沙门氏菌在小鼠中引起急性感染，通常会转化为慢性感染，其病程与伤寒相似。这种细菌寄生在脾脏、肝脏和排泄肠道的淋巴结上。我们证明了HM？在感染沙门氏菌的小鼠的脾脏、肝脏和骨髓中检测到HM？在感染后八周，当持续感染已经确定时，肝脏中含有沙门氏菌。在初步研究中，我们开发了一种流式细胞术来鉴定和分离HM？S来自其他细胞类型。这种新颖的方法以及已建立的方法使HM？S在疾病中。当前提案的目标是确定HM？这需要使这些细胞允许沙门氏菌复制。在感染性和非感染性情况下，Aims的完成在调节噬血和影响炎症过程的治疗发展中具有潜在的用途。

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.