Macrophage defense againt M. tuberculosis

巨噬细胞对结核分枝杆菌的防御

• 批准号: 7198023
• 负责人: Jennifer P Wang
• 金额: $ 12.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198023
• 关键词: Agonist; Alveolar Macrophages; Anti-Bacterial Agents; Apoptosis; Biological Assay; Breathing; Cause of Death; Cell Line; Cells; Cluster Analysis; Coculture Techniques; Condition; DNA Microarray Chip; DNA Microarray format; DNA Sequence; Dendritic Cells; Disease; Dominant-Negative Mutation; Dose; Endosomes; Ethambutol; Gene Expression; Gene Expression Profile; Genus Mycobacterium; Goals; Growth; Human; Human Activities; Imiquimod; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Interferon Type II; Investigation; Knowledge; Learning; Leukocytes; Ligands; Link; Liquid substance; Listeria monocytogenes; Luciferases; Lymphocyte; Messenger RNA; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Myelogenous; Nitric Oxide; Numbers; Oligonucleotides; Pathogenesis; Pathway interactions; Pattern; Phagocytosis; Pilot Projects; Play; Poly I-C; Population; Process; Production; Property; Proteins; Pyrazinamide; Range; Receptor Signaling; Reporter; Reporting; Research Personnel; Respiratory Burst; Rifampin; Role; Salmonella enterica; Signal Pathway; Signal Transduction; Specificity; Streptomycin; Surveys; TLR2 gene; TLR3 gene; TLR4 gene; Testing; Toll-Like Receptor 2; Toll-like receptors; Treatment Protocols; Tuberculosis; Vertebral column; analog; antimicrobial; base; cytokine; in vivo; insight; interest; isoniazid; killings; macrophage; microbial; microorganism; monocyte; mycobacterial; pathogen; programs; receptor; research study; response

DESCRIPTION (provided by applicant): Tuberculosis is a leading cause of death from infection worldwide. Investigations of interactions between Mycobacterium tuberculosis (Mtb) and human macrophages are fundamental for understanding tuberculosis pathogenesis. Immunostimulatory DNA sequences and their synthetic oligonucleotide analogs (CpG-ODN) have been shown to exert antibacterial effects in vitro and in vivo, and we discovered that CpG-ODN activate anti-mycobacterial activity in human monoeyte-derived macrophages (hMDM). The goals of this K08 project are to more fully characterize the mechanism(s) and magnitude of this CpG-ODN effect. Experiments will determine whether anti-mycobacterial responses are activated thorugh TLR9, the only receptor known to be activated by CpG-ODN. While murine macrophages can be activated by interferon (IFN)-gamma to kill intracellular mycobacteria in vitro, we and others have found that IFN-gamma, paradoxically potentiates intracellular growth of the pathogen. The mechanisms whereby human macrophages restrict Mtb remain uncertain, and new knowledge may be gained through delineating the mechanisms acitvated by CpG-ODN. We will determine if this response is broadly applicable to different Mtb strains, and if there are differences between the activity of hMDM and human alveolar macrophages (the initial host cell infected by Mtb in vivo). We will also test whether macrophage-like cell lines (THP-1) can be used to model the CpG-ODN response, since these cells would facilitate molecular studies of Toll-dependent signaling. Clues to the mechanism of this CpG-ODN effect will be sought in functional studies ofmacrophage activation and signaling, and using microarrays to interrogate the transcriptome of stimulated cells broadly. Finally, we will compare the effects of stimulation through different Toll receptors with a panel of ligands to look for similarities or differences compared with CpG-ODN, and to identify potential synergies. These studies will provide new basic knowledge of the innate anti-mycobacterial functions of human macrophages, and they will provide a rational basis for the discovery of new immunotherapeutic strategies for tuberculosis.

描述(申请人提供)：结核病是全球主要的感染致死原因。研究结核分枝杆菌(Mtb)与人巨噬细胞的相互作用是了解结核病发病机制的基础。免疫刺激DNA序列及其合成的寡核苷酸类似物(CpG-ODN)在体外和体内都具有抗菌作用，我们发现CpG-ODN对人单核细胞来源的巨噬细胞(HMDM)具有抗分枝杆菌活性。这个K08项目的目标是更全面地描述这种CpG-ODN效应的机制(S)和大小。实验将确定是否通过TLR9激活抗分枝杆菌反应，TLR9是已知的唯一被CpG-ODN激活的受体。虽然小鼠巨噬细胞可以被干扰素-γ激活，以在体外杀死细胞内的分枝杆菌，但我们和其他人发现，干扰素-γ矛盾地促进了病原体的细胞内生长。人巨噬细胞限制MTB的机制尚不清楚，通过阐明CpG-ODN激活的机制可能会获得新的认识。我们将确定这种反应是否广泛适用于不同的结核分枝杆菌菌株，以及HMDM和人肺泡巨噬细胞(体内感染结核分枝杆菌的初始宿主细胞)之间的活性是否存在差异。我们还将测试巨噬细胞样细胞系(THP-1)是否可以用来模拟CpG-ODN反应，因为这些细胞将促进Toll依赖信号的分子研究。这种CpG-ODN效应的机制将在巨噬细胞激活和信号传递的功能研究中寻找线索，并使用微阵列广泛询问刺激细胞的转录组。最后，我们将比较不同的Toll受体和一组配体的刺激效果，以寻找与CpG-ODN的相似或不同之处，并确定潜在的协同作用。这些研究将为人类巨噬细胞固有的抗分枝杆菌功能提供新的基础知识，并将为发现新的结核病免疫治疗策略提供合理的基础。