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.

概括   不变的天然杀伤细胞（Inkt细胞）表达不变的TCRα链，它们可以识别自我 CD1D提出的衍生物以及微生物糖脂抗原。缺乏inkt细胞的小鼠在 他们对肺炎链球菌的早期免疫反应，一种革兰氏阳性细菌 肺炎，败血症和其他疾病。我们已经表明，肺炎链球菌合成了一种糖脂 它们都是膜的主要成分，也是Inkt细胞的抗原。该化合物是葡萄糖基 二酰基甘油（GLC-DAG）含有疫苗酸，一种单饱和，18碳脂肪酸（C18：1），带有顺式 碳9和10之间的不饱和键。我们在B组链球菌（GBS）中发现了相同的抗原，A 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 未经测试。我们的第一个指导假设，并由仍然是初步的数据支持，是这些微生物 肺炎链球菌激活iNKT细胞需要抗原。可以理解的是，这是一个有争议的 鉴于Inkt细胞的自我反应性。此外，作为第二个指导假设，我们建议 某些类型的细菌，包括肺炎链球菌和GBS 通过关闭其宿主中疫苗酸的合成并通过创建分子嵌合体来糖脂 将宿主油酸掺入其膜糖脂中。尽管油酸仅与疫苗酸不同 仅在顺式不饱和键的位置时，无法识别出含油酸的GLC-DAG抗原 由inkt细胞。在具体目的中，我们结合了遗传学，生物化学和免疫测定法 外国抗原生物合成对于Inkt细胞激活和宿主防御的重要性。在AIM 2中，使用细菌 在不同条件和报告不饱和脂肪酸生物合成的菌株中生长，我们将探索 时间和器官在这两种革兰氏阳性病原体下关闭疫苗酸合成， 以及这对包括肺，大脑， 生殖道以及系统防御。在AIM 3中，我们将减少感染中油酸的合成 小鼠，确定这种营养素的可用性是否限制了受保护的Inkt细胞反应。在AIM 4中，我们 探索基于放置的糖脂识别的良好识别的生化基础 脂肪酸双键，该键在CD1D抗原结合凹槽中构建，因此不直接接触 与TCR。我们还将确定带有油酸的GLC-DAG抗原功能作为有效拮抗剂 由细菌合成的GLC-DAG抗原。 拟议的实验是基于我们的新颖发现，即由于保存代谢而产生的优势 当链球菌吸收宿主C18：1脂肪酸时，还提供了免疫进化机制。结果 通过提供对两种重要病原体及其的受保护反应的见解，会产生影响 与他们的主人的关系。数据不仅将对要求的要求有更多的了解 inkt细胞的激活，但它们还将阐明一种与 重要营养素的可用性。结果也可能对了解饮食和如何 肥胖会损害受保护的宿主反应。