MYCOKETIDES: NOVEL M TUBERCULOSIS PKS12 PRODUCT PRESENTED BY CD1C TO T CELLS

MYCOKETIDES：CD1C 至 T 细胞呈现的新型 M 结核病 PKS12 产品

• 批准号: 7955939
• 负责人: DAVID MOODY
• 金额: $ 0.74万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955939
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Affect; Alkanes; Antigens; Biology; Catalytic Domain; Cells; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Family; Funding; Genes; Genetic; Genome; Genus Mycobacterium; Grant; Human; Immune system; Institution; Label; Length; Lipids; Manuscripts; Mass Spectrum Analysis; Mediating; Medicine; Metabolic; Molecular; Mycobacterium tuberculosis; Pathway interactions; Pattern; Phospholipids; Physical condensation; Prevention; Production; Property; Proteins; Proteome; Publications; Research; Research Personnel; Resources; Series; Source; Structure; T-Cell Activation; T-Lymphocyte; Tuberculosis; United States National Institutes of Health; Ursidae Family; base; carbohydrate structure; isopentenyl pyrophosphate; member; mycobacterial; novel; pathogen; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Study of the lipid targets of CD1c-mediated T cell responses recently identified a mycobacterial phospholipid antigen whose carbohydrate structure precisely corresponded to mammalian mannosyl b-1-phosphodolichols (MPD), but contained an unusual lipid moiety. We have shown that this T cell antigen is a member of a family of branched, alkane lipids that vary in length (C30-34) and are produced by M. tuberculosis, M. bovis Bacille-Calmette-Guerin and other mycobacteria that grow within cells. Analysis of the fine structures of these mycobacterial antigens showed that the chemical features that distinguished them from mammalian MPDs were necessary for activation of CD1c-restricted T cells, but could not be accounted for by any known lipid biosynthetic pathway. Metabolic labeling and mass spectrometric analyses suggested a mechanism for elongating lipids in C5 increments by strictly alternating incorporation of C2 and C3 units, rather than isopentenyl pyrophosphate condensation. Inspection of the M. tuberculosis genome identified one gene pks12, which is predicted to make the largest protein in the proteome and to contain 12 catalytic domains necessary to carry out this multi-step synthesis. Genetic deletion and complementation showed that PKS12 was necessary and sufficient for antigen production and the resulting CD1c-mediated T cell activation, but did not affect synthesis of true isoprenols. These studies establish the genetic and enzymatic basis for a previously unknown type of mycobacterial polyketide, designated mycoketide, which represents a lipidic pathogen associated molecular pattern that allows mycobacterial recognition by the human immune system. These compounds provide new iinsight into the potential mechanism of CD1c-restricted T cell activation; they may bear relevance to prevention or treatment of AIDS. A series of synthetic compounds has been prepared and the manuscript describing their properties has been accepted for publication.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对CD 1c介导的T细胞应答的脂质靶点的研究最近鉴定了分枝杆菌磷脂抗原，其碳水化合物结构精确地对应于哺乳动物甘露糖基B-1-磷酸二醇（MPD），但含有不寻常的脂质部分。 我们已经表明，这种T细胞抗原是一个分支的，烷烃脂质的长度不同（C30-34），并由M。tuberculosis，M.牛卡介苗和其他在细胞内生长的分枝杆菌。 这些分枝杆菌抗原的精细结构的分析表明，区分它们与哺乳动物MPD的化学特征是必需的CD 1c限制性T细胞的激活，但不能占任何已知的脂质生物合成途径。 代谢标记和质谱分析表明，以C5增量延长脂质的机制是通过严格交替掺入C2和C3单元，而不是异戊烯基焦磷酸缩合。 检查M。结核病基因组鉴定了一个基因pks 12，预测该基因在蛋白质组中产生最大的蛋白质，并含有进行这种多步合成所必需的12个催化结构域。 基因缺失和互补表明，PKS 12是必要的和足够的抗原生产和由此产生的CD 1c介导的T细胞活化，但不影响合成的真正异戊烯醇。 这些研究建立了一种以前未知类型的分枝杆菌聚酮（称为分枝杆菌酮）的遗传和酶基础，它代表了一种与分枝杆菌病原体相关的分子模式，使分枝杆菌能够被人类免疫系统识别。这些化合物为CD 1c限制性T细胞活化的潜在机制提供了新的见解，它们可能与艾滋病的预防或治疗有关。已经制备了一系列合成化合物，描述其性质的手稿已被接受出版。