NKT cell mediated immunoregulation by symbiotic gut microbial glycosphingolipids

 描述(申请人提供)：哺乳动物宿主和它们的肠道微生物区系经过数千年的共同进化。虽然通常被描述为“共生”，但现在已知肠道微生物区系对宿主免疫的正常发展和免疫系统的动态平衡至关重要。微生物定植的失衡--生物失调--与各种炎症和自身免疫综合征有关，例如下胃肠道的炎症性肠病。在正常的免疫发育和对挑战的病理生理反应中，共生微生物产生的小分子，如脂质，可以在塑造免疫系统及其反应方面发挥关键作用。脆弱类杆菌是一种广泛存在于人类下胃肠道的细菌，在多种自身免疫性疾病中发挥着有趣的免疫调节生物学效应。在无菌小鼠中，野生型脆弱芽孢杆菌能抑制肠道自然杀伤T细胞(NKT细胞)的数量，并保护动物免受NKT细胞介导的结肠炎的侵袭，而鞘磷脂基因敲除菌株则不能提供这种保护。初步研究结果表明，脆性芽孢杆菌特有的鞘磷脂介体参与了这些保护机制。目前的提案描述了一项为期5年的指导性研究计划，重点是脆弱芽孢杆菌和其他共生类杆菌产生的独特鞘脂，并评估它们调节宿主免疫和保护宿主免受过度炎症的能力。这项工作的目的有三个：(1)获得一个全面的共生拟杆菌属鞘脂体组学图谱，并研究免疫调节鞘脂的生物合成途径；(2)化学合成共生鞘糖脂并评估对NKT细胞活性和增殖的调节；(3)研究共生神经鞘脂脂在免疫成熟和病理挑战时的NKT调节功能。为了实现这些目标，首席研究人员将在广泛了解分析化学和脂质介质免疫学的基础上获得微生物学和免疫学方面的知识和经验。教学和技术培训，加上丹尼斯·卡斯珀博士(主要导师)和一个科学咨询委员会的专家指导，将有助于该项目的成功完成，这是申请人走向独立的关键一步。

 DESCRIPTION (provided by applicant): Mammalian hosts and their intestinal microbiota have co-evolved over millennia. Although customarily described as "commensal," the microbiota of the gut is now known to be crucial for the normal development of host immunity and for the homeostasis of the immune system. An imbalance in microbial colonization-dysbiosis-is associated with diverse inflammatory and autoimmune syndromes, such as the inflammatory bowel diseases of the lower gastrointestinal tract. During normal immunologic development and pathophysiological reactions to challenges, small molecules produced by commensal microbes, such as lipids, can play crucial roles in shaping the immune system and its responses. Bacteroides fragilis, a well-studied resident of the human lower gastrointestinal tract, exerts interesting immune-modulating biological effects in various autoimmune diseases. In germ-free mice, wild-type B. fragilis monocolonization suppresses gut natural killer T cell (NKT cell) numbers and protects the animals from NKT cell-mediated colitis, whereas a sphingolipid- knockout strain does not provide such protection. Primary results imply that unique sphingolipid mediators originated from B. fragilis can contribute to these protective mechanisms. The current proposal describes a 5-year plan of mentored research focusing on the unique sphingolipids produced by B. fragilis and other commensal Bacteroidales and assessing their ability to modulate host immunity and protect the host from excessive inflammation. This work addresses three specific aims: (1) Acquire a comprehensive sphingolipidomic map of commensal Bacteroidales and investigate biosynthesis pathways of immunoregulatory sphingolipids, (2) Chemically synthesize commensal glycosphingolipids and assess regulation of NKT cell activity and proliferation and (3) Investigate the NKT-regulatory functions of commensal glycosphingolipids during immune maturation and upon pathological challenge. In order to attaining these goals, the principal investigator will gain knowledge and experience in microbiology and immunology based on a broad understanding of analytical chemistry and lipid mediator immunology. Didactic and technical training, in conjunction with expert mentorship by Dr. Dennis Kasper (primary mentor) and a scientific advisory committee, will aid in the successful completion of the project, which represents a key step toward independence of the applicant.