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：
8292621
负责人：
Corrella S Detweiler
金额：
$ 18.54万
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 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292621
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 (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.

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，肠道葡萄球菌（沙门氏菌）居住并重复在血型巨噬细胞中（HM¿），这些巨噬细胞吞噬了红细胞，血platelets，platelets，platelets，platelets，leukocytes及其前体细胞。我们的长期目标是确定沙门氏菌和HMS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。沙门氏菌会引起通常溶解成慢性感染的小鼠急性感染，并且疾病病程类似于伤寒。细菌定居脾脏，肝脏和耗尽肠道的淋巴结。我们证明了沙门氏菌感染的小鼠的囊，肝脏和骨髓中的HMS存在，并在肝脏感染后八周内确定了HM？s含有沙门氏菌，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术测定，以识别并将HM与脾脏分离。这种新颖的方法以及既定的方法可以使人们对HM在疾病中的作用进行新的探索。 The objects 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 bacteria replication, and 3) Identify regulatory pathways within HM¿ s needed to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。公共卫生相关性：内部提出的工作具有定义宿主 - 病原体相互作用的新颖和重要机制的潜力，不仅是沙门氏菌的，而且还通过推断其他触发HM累积的微生物，包括结核分枝杆菌，利什曼原虫物种和组织囊肿。拟议工作的长期意义在于它的潜力是提出新型的治疗方法，以促进HM？S积累的传染病和非感染疾病。