Hemophagocytic Macrophages and Systemic Salmonella Infection

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。我们已经证明，在小鼠中，沙门氏菌亚种鼠伤寒沙门氏菌(沙门氏菌)在噬血巨噬细胞(HM)内驻留和复制，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S HM是如何相互作用致病的。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。我们证实在沙门氏菌感染的小鼠的脾、肝和骨髓中存在S HM，并在确定持续感染的情况下，最迟在感染8周后的肝脏中发现含有沙门氏菌的S。在初步研究中，我们建立了一种从脾中鉴定和分离S的流式细胞术。这一新的方法论和既定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。目前应用的目标是1)确定吞噬血细胞的免疫学要求以及HM？积聚对小鼠伤寒病程的影响；2)确定HM？S在体内或在培养中因沙门氏菌感染而形成的HM？是否具有抗炎作用以及抗炎巨噬细胞是否允许细菌复制；以及3)确定HM？S内部使其能够允许沙门氏菌复制所需的调控通路。完成这些目标有可能阐明吞噬血细胞是否有益于宿主和沙门氏菌。此外，我们获得的信息可能用于开发治疗方法，调节吞噬血细胞功能，并影响感染和非感染环境下的炎症过程。 公共卫生相关性：这项研究中提出的工作不仅有可能为沙门氏菌定义新的和重要的宿主-病原体相互作用机制，而且可以通过推断引发HM积聚的其他微生物，包括结核分枝杆菌、利什曼原虫和组织胞浆菌。这项拟议工作的长期意义在于，它有可能为S所积累的传染病和非传染性疾病提出新的治疗方法。

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¿), 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 the spleen. This novel methodology along with established approaches enables new exploration of the role of HM¿s in disease. The objectives of the current application are to 1) Determine the immunological requirements for hemophagocytosis and the effect of HM¿ accumulation on the course of murine typhoid fever, 2) Establish whether HM¿s 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 HM¿s 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. PUBLIC HEALTH RELEVANCE: The work proposed within has the potential to define novel 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 work is its potential to suggest novel therapeutic approaches to infectious and non-infectious diseases in which HM¿s accumulate.