Hemophagocytic Macrophages and Systemic Salmonella Infection

噬血细胞巨噬细胞和全身性沙门氏菌感染

• 批准号: 8805824
• 负责人: Corrella S Detweiler
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805824
• 关键词: 3-Dimensional; Acute; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Biological Assay; Biological Models; Blood Platelets; Bone Marrow; Cell Culture Techniques; Cells; Characteristics; Chemicals; Chronic; Communicable Diseases; Confocal Microscopy; Data; Disease; Erythrocytes; Flow Cytometry; Genetic; Goals; Gram-Negative Bacteria; Health; Histiocytosis haematophagic; Histoplasma capsulatum; Human; Immune system; Infection; Inflammation; Inflammatory; Intestines; Leishmania; Leukocytes; Life; Lipids; Liver; Macrophage Activation; Maintenance; Medical; Methodology; Methods; Microbe; Modeling; Mus; Mycobacterium tuberculosis; Pathogenesis; Pathology; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Phenotype; Predisposition; Protocols documentation; Protozoa; Regulatory Pathway; Research; Role; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Small Interfering RNA; Spleen; Testing; Text; Tissues; Transgenic Mice; Typhoid Fever; Vesicle; Virus; Work; activating transcription factor; base; cytokine; fungus; in vivo; lymph nodes; macrophage; monocyte; mouse model; novel; novel strategies; novel therapeutic intervention; pathogen; precursor cell; prevent; research study; residence; response; therapy development

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.

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，在小鼠体内，沙门氏菌亚种鼠伤寒沙门氏菌存在于噬血细胞巨噬细胞(HMΦ)内并复制，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HMΦS是如何相互作用导致疾病的。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。我们在沙门氏菌感染的小鼠的脾、肝和骨髓中发现了HMΦS，并在肝脏中发现了HMΦS，直到沙门氏菌感染8周后，才建立了持续感染的证据。在初步研究中，我们建立了一种从脾组织中鉴定和分离HMΦS的流式细胞术。这一新的方法学以及已有的方法使我们能够对HMΦS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HMΦ积聚对小鼠伤寒病程的影响；2)确定针对沙门氏菌感染在体内或在培养中形成的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；以及3)确定HMΦS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。