Role of Tuberculosinyl Metabolites in M. Tuberculosis Virulence

结核菌素代谢物在结核分枝杆菌毒力中的作用

• 批准号: 8996551
• 负责人: DAVID Branch MOODY
• 金额: $ 54.43万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996551
• 关键词: ATP phosphohydrolase; Acids; Adenosine; Anabolism; Antibodies; Antigens; Bacteria; Biological; Biological Assay; Breathing; Cells; Cellular biology; Cessation of life; Characteristics; Chemicals; Data; Diagnosis; Diagnostic tests; Disease; Enzymes; Epidemic; Family; Genes; Genetic; Genus Mycobacterium; Growth; Health; Homologous Gene; Host Defense; Human; Hydrolase; In Vitro; Infection; Lipids; Lung; Measures; Mediating; Membrane; Membrane Fusion; Molecular; Molecular Target; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Nature; Nitrogen; Nuclear Magnetic Resonance; Nucleosides; Organism; Outcome; Oxygen; Pathogenicity; Patients; Peru; Phagolysosome; Phagosomes; Process; Proteins; Protons; Publishing; Research; Role; Serum; Structure; Testing; Transfection; Tuberculosis; Urine; Vaccines; Variant; Virulence; Virulence Factors; Virulent; abstracting; adenosine receptor activation; base; chemical genetics; cohort; extracellular; in vivo; inhibitor/antagonist; insight; killings; macrophage; mycobacterial; novel diagnostics; pathogen; prenyl; research study; tool; tuberculosis treatment

 DESCRIPTION (provided by applicant): Role of tuberculosinyl metabolites in M. tuberculosis virulence Abstract Among all types of mycobacteria, Mycobacterium tuberculosis is the world's most prevalent and deadly pathogen. To find the particular molecules that enable its pathogenicity, we compared all detectable lipids in M. tuberculosis to those in a non-pathogenic vaccine strain (BCG). This subtractive screen identified a previously type of molecule called tuberculosinyl adenosine (TbAd) as well as the genes (Rv3377c, Rv3378c) that produce it. Although TbAd was overlooked in a century of tuberculosis research, our preliminary data show that TbAd is one of the most abundant lipids and is produced as six structurally related subfamilies. Published data show that M. tuberculosis is unique among mycobacteria in its ability to survive within the phagosomes of infected macrophages, based in its blockade of acid-mediated bacterial killing by macrophages. Our preliminary data show that TbAd is sufficient to block acidification of macrophage phagosomes. Therefore, we posit that TbAd and related tuberculosinyl metabolites are the long sought molecules that influence M. tuberculosis' unique ability to escape intracellular death. Here we propose to discover new tuberculosinyl metabolites in M. tuberculosis and determine their natural structures. Using synthetic TbAd and human macrophages, we will determine the cellular mechanism by which TbAd selectively inhibits phagosome acidification, while still allowing M. tuberculosis to be taken up into its phagosomal niche. Using M. tuberculosis lacking the biosynthetic enzymes (Rv 3378c, Rv3377c), we will measure the influence of TbAd in the outcome of natural infections. Last, we will test tuberculosinyl metabolites as targets for new diagnostic tests for human tuberculosis. Several features suggest that TbAd and TbAd-specific antibodies could be a highly specific chemical marker or infection. TbAd is abundantly secreted by M. tuberculosis, but is lacking in other pathogens that mimic tuberculosis. Therefore, we will detect TbAd and TbAd specific antibodies in serum and urine from a well-characterized patient cohort in Lima, Peru and in mice.

 描述（由适用提供）：结核菌代谢物在结核分枝杆菌病毒中的作用在所有类型的分枝杆菌中，结核分枝杆菌是世界上最普遍，最致命的病原体。为了找到能够使其致病性的特定分子，我们将结核分枝杆菌中的所有可检测的脂质与非致病疫苗菌株（BCG）中的脂质进行了比较。该减法屏幕确定了以前类型的TBAD在一个世纪的结核病研究中被忽略了，我们的初步数据表明，TBAD是最丰富的脂质之一，并作为六个结构相关的亚家族生产。已发表的数据表明，结核分枝杆菌在分枝杆菌中具有独特的能力，其能够在感染巨噬细胞的吞噬体中生存，这是基于巨噬细胞杀死酸介导的细菌的阻断。我们的初步数据表明，TBAD足以阻止巨噬细胞吞噬体的酸化。因此，我们认为TBAD和相关的结核素代谢产物是影响结核分枝杆菌逃避细胞内死亡的独特能力的长scart分子。在这里，我们建议在结核分枝杆菌中发现新的结核素代谢物并确定其自然结构。使用合成TBAD和人类巨噬细胞，我们将确定TBAD选择性抑制吞噬体酸化的细胞机制，同时仍允许结核分枝杆菌被吸收到其吞噬小裂中。使用缺乏生物合成酶（RV 3378C，RV3377C）的结核分枝杆菌，我们将测量TBAD在自然感染结果中的影响。最后，我们将测试结核素代谢产物作为人类结核病的新诊断测试的靶标。几个特征表明TBAD和TBAD特异性抗体可能是高度特异性的化学标志物或感染。 TBAD显然是结核分枝杆菌的分泌，但缺乏模仿结核病的其他病原体。因此，我们将检测到利马，秘鲁和小鼠中特征良好的患者队列中血清和尿液中的TBAD和TBAD特异性抗体。