Mucosal associated invariant T (MAIT) cells in Vibrio cholerae infection and vaccination

霍乱弧菌感染和疫苗接种中的粘膜相关不变 T (MAIT) 细胞

• 批准号: 9926810
• 负责人: Daniel Ted Leung
• 金额: $ 35.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-22 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926810
• 关键词: Accounting; Acute; Adult; Affect; Antibodies; Antibody Formation; Antibody Response; B cell differentiation; B-Lymphocytes; Bangladesh; Bangladeshi; CD8B1 gene; Cells; Cessation of life; Child; Cholera; Cholera Vaccine; Clonal Expansion; Collaborations; Country; Data; Development; Elderly; Family; Genes; Genetic Transcription; Heterogeneity; Human; Immune response; Immune system; Immunoglobulin Class Switching; In Vitro; Individual; Infection; Intestinal Mucosa; Ligands; Link; Liver; Lymphocyte; Mediating; Methods; Mucous Membrane; Natural Immunity; O Antigens; Oral; Peripheral; Phenotype; Pilot Projects; Play; Polysaccharides; Proteins; Reporting; Research; Role; Scientist; Specificity; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; TNFSF5 gene; Testing; Ursidae Family; Vaccination; Vaccines; Vibrio cholerae; Vibrio cholerae infection; Vitamin B Complex; adaptive immune response; adaptive immunity; burden of illness; cytokine; diarrheal disease; enteric infection; enteric pathogen; experimental study; improved; interleukin-21; international center; mesenteric lymph node; novel; pathogen; prevent; response; transcription factor; transcriptome sequencing; transcriptomics; vaccine efficacy

Project Summary/Abstract Cholera is an acute dehydrating diarrheal disease caused by infection with Vibrio cholerae. It is endemic in over 50 countries, affecting up to 3 million people and causing more than 100,000 deaths annually worldwide. Currently available oral cholera vaccines (OCV) achieve a lower efficacy and duration of protection in young children compared to that seen in older children and adults, possibly due to the inability of young children to mount polysaccharide-specific antibody responses. We have recently reported that mucosal-associated invariant T (MAIT) cells are activated in cholera and are associated with higher class-switched V. cholerae polysaccharide-specific antibody responses. In pilot studies, we have identified a subset of MAIT cells that express genes associated with B cell help. Additionally, in preliminary in vitro experiments, we show that MAIT cells can induce B cells to differentiate and produce antibodies. Thus, we hypothesize that a subset of MAIT cells, when activated following infection or vaccination, undergo clonal expansion and provide help to B cells through MR1-dependent and -independent interactions to enhance polysaccharide-specific antibody production. In collaboration with the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), we propose to determine the role that MAIT cells play in the adaptive response against V. cholerae infection and vaccination. In Aim 1, we will characterize the clonal expansions of MAIT cells during human V. cholerae infection and oral cholera vaccination. We will test the hypothesis that there is a subset of MAIT cells that express factors consistent with B cell help, and that this subset has lower activation and expansion in young child vaccinees compared to older child vaccinees and infected young children. In Aim 2, we will determine the mechanisms through which MAIT cells affect B cell differentiation and antibody production. We will test the hypotheses that MAIT cells provide help to B cells through both MR1-dependent and MR1- independent (cytokine-mediated) interactions with B cells, and that MAIT cells of young children have deficits in one or more of these mechanisms compared to MAIT cells in older children. At the completion of these studies, we will have gained new information on the capacity of MAIT cells to impact polysaccharide-specific antibody responses, which are associated with protection against cholera. This information has the potential to critically inform the development of better vaccine strategies targeted at preventing cholera and other enteric infections in young children.

项目概要/摘要 霍乱是由霍乱弧菌感染引起的一种急性脱水性腹泻病。它流行于 影响全球 50 多个国家，影响多达 300 万人，每年造成超过 10 万人死亡。 目前可用的口服霍乱疫苗 (OCV) 对年轻人的功效和保护持续时间较低 与年龄较大的儿童和成人相比，儿童的情况可能是由于幼儿无法 建立多糖特异性抗体反应。我们最近报道了与粘膜相关的 不变 T (MAIT) 细胞在霍乱中被激活，并与更高类别转换的霍乱弧菌相关 多糖特异性抗体反应。在试点研究中，我们已经确定了 MAIT 细胞的一个子集 表达与 B 细胞帮助相关的基因。此外，在初步体外实验中，我们表明 MAIT 细胞可以诱导B细胞分化并产生抗体。因此，我们假设 MAIT 的一个子集 细胞在感染或疫苗接种后被激活时，会进行克隆扩增并为 B 细胞提供帮助 通过MR1依赖和独立的相互作用来增强多糖特异性抗体 生产。与孟加拉国国际腹泻病研究中心合作 (ICDDR,B)，我们建议确定 MAIT 细胞在针对霍乱弧菌的适应性反应中所发挥的作用 感染和疫苗接种。在目标 1 中，我们将描述人类 V 期间 MAIT 细胞的克隆扩增。 霍乱感染和口服霍乱疫苗接种。我们将检验存在 MAIT 细胞子集的假设 表达与 B 细胞帮助一致的因子，并且该亚群在 幼儿疫苗接种者与年龄较大的儿童疫苗接种者和受感染幼儿的比较。在目标 2 中，我们将 确定 MAIT 细胞影响 B 细胞分化和抗体产生的机制。我们 将测试 MAIT 细胞通过 MR1 依赖性和 MR1- 向 B 细胞提供帮助的假设 与 B 细胞的独立（细胞因子介导的）相互作用，并且幼儿的 MAIT 细胞存在缺陷 与年龄较大儿童的 MAIT 细胞相比，这些机制中的一种或多种。完成这些工作后 研究中，我们将获得有关 MAIT 细胞影响多糖特异性的能力的新信息 抗体反应，与预防霍乱有关。该信息有可能 为制定更好的疫苗策略提供重要信息，以预防霍乱和其他肠道疾病 幼儿感染。