Hemophagocytic Macrophages and Systemic Salmonella Infection

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）在噬血细胞巨噬细胞（HMΦ）中存在并复制，噬血细胞巨噬细胞是吞噬红细胞、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HMΦs如何相互作用导致疾病。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。我们证实了沙门氏菌感染小鼠的脾脏、肝脏和骨髓中存在HMΦs，并在肝脏感染后8周发现HMΦs含有沙门氏菌，此时已经建立了持续感染。在初步研究中，我们开发了一种流式细胞术来鉴定和分离脾脏中的HMΦs。这种新颖的方法以及已建立的方法可以对HMΦs在疾病中的作用进行新的探索。当前应用的目的是：1)确定噬血细胞作用的免疫学要求以及HMΦ积累对小鼠伤寒病程的影响；2)确定体内或培养中响应沙门氏菌感染形成的HMΦs是否具有抗炎作用，以及抗炎巨噬细胞是否允许细菌复制；3)确定HMΦs中允许沙门氏菌复制所需的调控途径。这些目的的完成有可能阐明噬血作用是否对宿主和沙门氏菌有益。此外，我们获得的信息有潜在的用途，在治疗的发展，调节噬血和影响炎症的过程在感染性和非感染性情况下。

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 (HMΦ), which are macrophages that have engulfed erythrocytes, platelets, leukocytes and their precursor cells. Our long-term goal is to determine how Salmonella and HMΦs 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 HMΦs within the spleen, liver and bone marrow of Salmonella - infected mice and identified HMΦs 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 HMΦs from the spleen. This novel methodology along with established approaches enables new exploration of the role of HMΦs in disease. The objectives of the current application are to 1) Determine the immunological requirements for hemophagocytosis and the effect of HMΦ accumulation on the course of murine typhoid fever, 2) Establish whether HMΦs formed in response to Salmonella infection in vivo or in culture become anti-inflammatory and whether anti-inflammatory macrophages are permissive for bacterial replication, and 3) Identify regulatory pathways within HMΦs needed to make them permissive for Salmonella replication. Completion of these Aims has the potential to elucidate whether hemophagocytosis benefits the host as well as Salmonella. In addition, the information we acquire has potential use in the development of treatments that modulate hemophagocytosis and influence the course of inflammation in infectious and non-infectious circumstances.