Host nutrients permit immune evasion of NKT cell anti-bacterial responses

宿主营养物质允许免疫逃避 NKT 细胞抗菌反应

• 批准号: 10089228
• 负责人: MITCHELL KRONENBERG
• 金额: $ 61.54万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-17 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089228
• 关键词: Acids; Anabolism; Antibacterial Response; Antigens; Autoantigens; Bacteria; Binding; Biochemical; Biochemistry; Brain; CD1d antigen; Carbon; Cells; Child; Chimera organism; Cytotoxic T-Lymphocytes; Data; Diet; Diglycerides; Disease; Elderly; Enzyme Inhibitor Drugs; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic; Glycolipids; Gram-Positive Bacteria; Growth; Host Defense; Immune Evasion; Immune response; Immune system; Immunology procedure; Impairment; In Vitro; Infection; Inflammation; Integration Host Factors; Light; Lung; Membrane; Meningitis; Metabolic; Microbe; Molecular; Mus; Newborn Infant; Nutrient; Obesity; Oleic Acids; Organ; Pneumonia; Reporting; Resistance; Role; Savings; Sepsis; Serum; Side; Site; Specificity; Stearoyl-CoA Desaturase; Streptococcal Infections; Streptococcus; Streptococcus Group B; Streptococcus pneumoniae; Structure; T cell response; T-Cell Activation; TCR Activation; Unsaturated Fatty Acids; Work; antigen binding; bacterial resistance; base; cell type; cytokine; experimental study; fatty acid biosynthesis; in vivo; inhibitor/antagonist; insight; microbial; microorganism antigen; mutant; novel; pathogen; pi bond; reproductive tract; response; sugar; unsaturated bonds

Summary    Invariant natural killer T cells (iNKT cells) express an invariant TCR α chain and they can recognize self- derived as well as microbial glycolipid antigens presented by CD1d. Mice lacking iNKT cells are impaired in their early immune response against Streptococcus pneumoniae, a gram-positive bacterium responsible for pneumonia, sepsis and other diseases. We have shown that S. pneumoniae synthesizes a glycolipid that is a both a major component of their membrane and an antigen for iNKT cells. This compound is a glucosylated diacylglycerol (Glc-DAG) containing vaccenic acid, a mono-unsaturated, 18 carbon fatty acid (C18:1) with a cis unsaturated bond between carbons 9 and 10. We found an identical antigen in group B streptococcus (GBS), a  leading cause of meningitis in children, although the role of iNKT cells in defense from this pathogen remains  untested.  Our first guiding hypothesis, supported by data that are still preliminary, is that these microbial antigens are required for iNKT cell activation by S. pneumoniae. This understandably has been a controversial issue, in light of the self-reactivity of iNKT cells. Furthermore, as a second guiding hypothesis, we propose that some types of bacteria, including S. pneumoniae and GBS, avoid iNKT cell recognition of their membrane glycolipid by turning off synthesis of vaccenic acid in their hosts and by creating a molecular chimera by incorporating host oleic acid into their membrane glycolipid. Although oleic acid only differs from vaccenic acid only in the placement of the cis unsaturated bond, the Glc-DAG antigen with oleic acid cannot be recognized by iNKT cells. In the specific aims, we combine genetics, biochemistry and immune assays to demonstrate the importance of foreign antigen biosynthesis for iNKT cell activation and host defense. In Aim 2, using bacteria grown under different conditions and strains that report on unsaturated fatty acid biosynthesis, we will explore the timing and the organ(s) under which these two gram-positive pathogens turn off vaccenic acid synthesis, and the effect this has on the iNKT cell response and host defense in different sites, including the lung, brain, reproductive tract, as well as systemic defense. In Aim 3, we will reduce synthesis of oleic acid in infected mice, to determine if increased availability of this nutrient limits the protective iNKT cell response. In Aim 4, we explore the biochemical basis for the fine specificity of recognition of glycolipids based on the placement of the fatty acid double bond, which is buried in the CD1d antigen binding groove and therefore not directly in contact with the TCR. We also will determine if the Glc-DAG antigens with oleic acid function as effective antagonists of the Glc-DAG antigen synthesized by the bacteria. The proposed experiments are based on our novel finding that the advantage due to metabolic saving when Strep bacteria take up host C18:1 fatty acid also provides an immune evasion mechanism. The results will have impact by providing insights into the protective responses to two important pathogens and their relationships with their hosts. The data will not only deliver a greater understanding of the requirements for iNKT cell activation, but also, they will elucidate a pathogen immune evasion mechanism that is tied to the availability of an important nutrient. The results may also have implications for understanding how diet and obesity impair a protective host response.

总结   不变的自然杀伤T细胞（iNKT细胞）表达不变的TCR α链，它们可以识别自身免疫缺陷。 衍生的以及由CD 1d呈递的微生物糖脂抗原。缺乏iNKT细胞的小鼠， 他们对肺炎链球菌的早期免疫反应，肺炎链球菌是一种革兰氏阳性细菌， 肺炎、败血症和其他疾病。我们证明了S.肺炎杆菌合成糖脂， 它们的细胞膜的主要成分和iNKT细胞的抗原。该化合物是葡萄糖基化的 含有异油酸的甘油二酯（Glc-DAG），异油酸是一种单不饱和的18碳脂肪酸（C18：1），具有顺式 碳9和碳10之间的不饱和键。我们在B群链球菌（GBS）中发现了一种相同的抗原， 这是儿童脑膜炎的主要原因，尽管iNKT细胞在防御这种病原体中的作用仍然存在 我们的第一个指导性假设，由仍然是初步的数据支持，是这些微生物 抗原是S.肺炎。可以理解，这是一个有争议的 根据iNKT细胞的自身反应性。此外，作为第二个指导假设，我们提出， 一些类型的细菌，包括S。pneumoniae和GBS，避免iNKT细胞识别其膜 通过关闭宿主体内异油酸的合成， 将宿主油酸整合到它们的膜糖脂中。尽管油酸与异油酸仅不同 只有在顺式不饱和键的位置，含油酸的Glc-DAG抗原不能被识别 iNKT细胞。在具体目标上，我们将联合收割机的遗传学、生物化学和免疫学方法相结合， 外源抗原生物合成对于iNKT细胞活化和宿主防御重要性。在目标2中，使用细菌 生长在不同的条件和菌株，报告不饱和脂肪酸的生物合成，我们将探讨 这两种革兰氏阳性病原体关闭异辛酸合成的时间和器官， 以及这对iNKT细胞反应和不同部位的宿主防御的影响，包括肺，脑， 生殖道，以及系统防御。在目标3中，我们将减少受感染的小鼠中油酸的合成， 小鼠，以确定这种营养素的可用性增加是否限制了保护性iNKT细胞反应。在目标4中， 探索基于糖脂的位置的识别的精细特异性的生化基础， 脂肪酸双键，埋在CD 1d抗原结合沟中，因此不直接接触 与TCR。我们还将确定是否Glc-DAG抗原与油酸功能作为有效的拮抗剂 由细菌合成的Glc-DAG抗原。 所提出的实验是基于我们的新发现，由于代谢节省的优势， 当链球菌摄取宿主C18：1脂肪酸时，也提供了免疫逃避机制。结果 将通过提供对两种重要病原体的保护性反应及其 与主人的关系。这些数据不仅可以更好地了解 iNKT细胞激活，而且，他们将阐明病原体免疫逃避机制，这是联系在一起的。 一种重要的营养物质。研究结果也可能对理解饮食和 肥胖会削弱宿主的保护性反应。