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

项目摘要/摘要 霍乱是一种急性脱水腹泻疾病，由霍乱弧菌感染引起。它在中国是地方病 在50多个国家，每年有多达300万人受到影响，并造成100 000多人死亡。 目前可用的口服霍乱疫苗(OCV)对年轻人的效力和保护期较低 儿童与年龄较大的儿童和成年人相比，可能是由于幼儿没有能力 安装多糖特异性抗体反应。我们最近报道了粘膜相关的 不变T细胞(MAIT)在霍乱中被激活，并与较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细胞相关的基因有帮助。此外，在初步的体外实验中，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 细胞在感染或接种后被激活时，会进行克隆性增殖，并为B细胞提供帮助 通过MR1依赖和非依赖相互作用增强多糖特异性抗体 制作。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细胞在对霍乱弧菌的适应性反应中所起的作用。 感染和接种疫苗。在目标1中，我们将描述MAIT细胞在人类V. 霍乱感染和口服霍乱疫苗接种。我们将测试存在MAIT细胞子集的假设 表达与B细胞帮助一致的因子，并且这个亚群在 幼儿疫苗接种者与年龄较大的儿童疫苗接种者和感染的幼儿相比。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 将验证MAIT细胞通过MR1依赖和MR1-2向B细胞提供帮助的假设 与B细胞的独立(细胞因子介导)相互作用，幼儿MAIT细胞存在缺陷 在一个或多个这些机制中，与年龄较大的儿童的MAIT细胞相比。在完成这些操作后 研究，我们将获得关于MAIT细胞影响多糖特异性的能力的新信息 抗体反应，这与预防霍乱有关。这些信息有可能 关键地告知制定更好的疫苗战略，以预防霍乱和其他肠道疾病 幼儿感染。

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.