Hemophagocytic Macrophages and Systemic Salmonella Infection

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（Salmonella）存在于噬血细胞巨噬细胞（HMΦ）内并在其中复制，所述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。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HMΦs在沙门氏菌感染的小鼠的脾、肝和骨髓中的存在，并在肝中鉴定出含有沙门氏菌的HMΦs，直到感染后8周，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测定法来鉴定和分离来自脾脏的HMΦ。这种新的方法沿着与已建立的方法使得能够对HMΦ在疾病中的作用进行新的探索。本申请的目的是1）确定噬血细胞作用的免疫学要求和HMΦ积累对鼠伤寒过程的影响，2）确定体内或培养物中响应沙门氏菌感染而形成的HMΦ是否具有抗炎性，以及抗炎巨噬细胞是否允许细菌复制，和3）确定HMΦ内使其允许沙门氏菌复制所需的调节途径。这些目标的完成有可能阐明噬血作用是否有益于宿主以及沙门氏菌。此外，我们获得的信息在开发调节噬血细胞作用和影响感染和非感染情况下炎症过程的治疗方面具有潜在用途。

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 (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.