Hemophagocytic Macrophages and Systemic Salmonella Infection

噬血细胞巨噬细胞和全身性沙门氏菌感染

基本信息

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
项目类别：
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

项目摘要

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（适用提供）：许多对人类健康重要的细菌病原体通过生活在白细胞中逃避免疫学系统。沙门氏菌Enterica是一种革兰氏阴性细菌，其中包括人伤寒的属属，位于一类称为巨噬细胞的白细胞中。我们已经证明，在小鼠中，肠孢子菌（Salmonella）（沙门氏菌）居住并在血液噬菌体（HMφ）内居住并复制，这些巨噬细胞是吞噬红细胞，血platelets，platelets，platelets，leukocytes，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HMφ如何相互作用以引起疾病。感染沙门氏菌的小鼠是野外遇到的天然宿主 - 病原体模型系统。沙门氏菌会导致小鼠的急性感染，通常会溶解成慢性感染，并且疾病病程类似于伤寒。细菌在散布肠道的囊，肝脏和淋巴结中定居。我们证明了沙门氏菌感染的小鼠的囊，肝脏和骨髓中的HMφS，并在肝脏感染后八周内鉴定出含有沙门氏菌的HMφS，并确定了持续性感染。在初步研究中，我们开发了一种流式细胞仪测定法，以识别和将HMφ与SLEEN分离。这种新颖的方法加上既定的方法，可以新探索HMφ在疾病中的作用。当前应用的对象是1）确定胞噬细胞增多症的免疫学要求以及HMφ积累对鼠伤寒鼠的影响的影响，2）确定在体内或培养中响应沙门氏菌感染或培养中形成的HM或是否在抗炎和抗炎中是否需要进行抗炎型疫苗，并且是否识别了抗炎性疫苗。使它们允许沙门氏菌复制。这些目标的完成有可能阐明胞吞作用是否使宿主和沙门氏菌受益。此外，我们获取的信息在调节胞吞作用并影响传染性和非感染情况的炎症过程的治疗过程中可能使用。