Modulation of in vivo MAIT cell responses with diverse MR1 ligands

用不同的 MR1 配体调节体内 MAIT 细胞反应

基本信息

批准号：
10626969
负责人：
Michael George Constantinides
金额：
$ 22.19万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-24 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626969
关键词：
Affect Agonist Allergens Asthma Bacteria Bacterial Antibiotic Resistance Bacterial Pneumonia Binding Birth Cell Line Cell physiology Characteristics Child Coculture Techniques Development Disease Docking Evaluation Health Human IL17 gene Immunity In Vitro Individual Inflammatory Life Ligands Lung Lung diseases MHC Class I Genes Mediating Mucous Membrane Mus Pathway interactions Persons Pharmaceutical Preparations Physiological Pneumonia Population Predisposition Prevalence Production Respiratory Tract Infections Riboflavin Schiff Bases Stimulus Surface T cell response T-Cell Development T-Lymphocyte Therapeutic Vaccines Validation Viral Pneumonia Virus Diseases Vitamins Work airway inflammation asthma model cytokine fungus immune function immunoregulation in vitro activity in vivo innovation microbial microbial products mortality mouse model novel pathogen pneumonia model prevent respiratory pathogen response small molecule libraries virtual

项目摘要

Project Summary Pulmonary diseases are a major health concern, with pneumonia the leading infectious cause of mortality for young children. Respiratory infections in early life are associated with increased susceptibility to asthma; an inflammatory disorder that afflicts more than 250 million people each year and has increased in prevalence during the past decade. However, the lack of vaccines for many of the pathogens that cause pneumonia and the emergence of antibiotic resistant bacteria necessitate alternative approaches. Mucosal-associated invariant T (MAIT) cells comprise a substantial effector population within human lungs, reaching up to 9% of pulmonary T cells in healthy individuals. MAIT cells recognize microbial derivatives of riboflavin (vitamin B2) synthesis presented by the MHC class-I related (MR1) molecule. Due to the broad conservation of this biosynthetic pathway among bacteria and fungi, MAIT cells promote immunity to a wide array of respiratory pathogens. MAIT cells have also been implicated in preventing asthma and reducing airway inflammation. However, in addition to presenting derivatives of vitamin synthesis, recent work has demonstrated that MR1 can also bind drugs and drug metabolites that can either be agonists or non-agonists of MAIT cells, suggesting that drugs may hinder MR1-mediated presentation of endogenous microbial metabolites, which could have implications for the susceptibility to pneumonia or asthma. While derivatives of riboflavin synthesis increase MAIT cell abundance and cytokine production in vivo, the instability of these molecules results in rapid degradation under physiological conditions, limiting their therapeutic potential. We will perform the first evaluation of how MR1 binding drugs impact the development of MAIT cells and the first in vivo assessment of how non-vitamin derived MR1 ligands affect MAIT cell responses to physiologically relevant pulmonary conditions. We will also perform the most extensive virtual screen to date for novel MAIT cell agonists using Reactive Docking to simulate the formation of a Schiff base with K43 of MR1 – a key characteristic of the strongest known MAIT cell agonists the promotes MR1 folding for surface expression. Following validation of MR1 binding and MAIT cell agonistic activity in vitro, the immunomodulatory effects of these novel agonists will be established in vivo. We hypothesize that we will identify novel MAIT cell agonists that enhance pulmonary immunity, while administration of non-agonistic MR1 binding drugs can inhibit the development and function of MAIT cells in vivo.

项目摘要肺部疾病是主要的健康问题，肺炎是导致死亡的主要感染原因年幼的孩子。早期生命中的呼吸道感染与哮喘的敏感性增加有关。炎症性疾病每年遭受超过2.5亿人的困扰，并且患病率有所增加在过去的十年中。但是，许多导致肺炎和的病原体缺乏疫苗抗生素抗性细菌的出现必要的替代方法。粘膜相关的不变t （MAIT）细胞包含人肺中的大量效应子群，最多达9％健康个体中的细胞。 Mait细胞识别核黄素（维生素B2）合成的微生物衍生物由MHC I类相关（MR1）分子提出。由于这种生物合成的广泛保守细菌和真菌之间的途径，MAIT细胞促进了各种呼吸道病原体的免疫组织化学。梅特细胞也与防止哮喘和减少气道注射有关。但是，除了呈现维生素合成的衍生物，最近的工作表明MR1也可以结合药物，并且可以是激动剂或非激动剂的药物代谢物，表明药物可能会阻碍 MR1介导的内源性微生物代谢产物的表现，这可能对对肺炎或哮喘的敏感性。核黄素合成的衍生物增加了MAIT细胞滥用在体内产生细胞因子，这些分子的不稳定性在生理下会迅速降解条件，限制其治疗潜力。我们将对MR1结合药物的首次评估影响MAIT细胞的发展和对非维生素如何衍生MR1配体的首次体内评估影响MAIT细胞对物理相关的肺部条件的反应。我们还将表现最多迄今为止，新型Mait细胞激动剂使用反应式对接模拟了大量虚拟屏幕具有MR1的K43的Schiff基础 - 强烈已知的Mait细胞激动剂的关键特征促进 MR1折叠表达表达。在体外验证MR1结合和MAIT细胞激动活性之后，这些新型激动剂的免疫调节作用将在体内建立。我们假设我们将确定增强肺免疫学的新型MAIT细胞激动剂，而施用非阳性MR1 结合药物可以抑制MAIT细胞在体内的发育和功能。