Innate and early B cell responses to V. cholerae

描述（由申请人提供）：霍乱仍然是一个重要的原因，霍乱疾病，证明了它最近出现在地震后的海地。科学和政策领导人越来越多地呼吁使用预防性策略，例如对霍乱等霍乱疾病进行疫苗接种，但目前的霍乱疫苗存在免疫局限性。最重要的是，口服霍乱疫苗产生的保护作用持续时间较短-与自然感染霍乱弧菌形成对比，后者产生持久的免疫力。 在这里提出的研究中，我们试图确定天然感染与霍乱疫苗接种后先天和B细胞免疫反应的最早差异。我们还旨在确定这些早期差异中哪些对长期免疫记忆的后续发展最关键。了解这些早期差异可以解释为什么只有自然感染霍乱弧菌才能引起长期记忆B细胞反应，这对预防霍乱很重要。 由于霍乱弧菌是一种人类限制性病原体，因此临床研究对于解决这个问题至关重要。我们建议利用马萨诸塞州总医院/哈佛医学院（MGH/HMS）、孟加拉国国际腹泻病研究中心（ICDDR，B）、埃默里疫苗中心和麻省理工学院/哈佛大学布罗德研究所之间的现有合作来解决人类中的这个问题。具体而言，我们将比较霍乱感染后与接种疫苗后粘膜组织中先天免疫应答的激活，并评估这些差异中哪些与霍乱患者的长期记忆B细胞应答相关。我们还将比较患者和疫苗接种者的抗体分泌细胞（ASC）反应。免疫球蛋白基因的克隆和这些克隆抗体的生产，从个人的ASC可能会提高我们的理解之间的差异，B细胞反应霍乱患者和疫苗接种者，所产生的抗体也可能提供诊断和治疗的潜力的工具。这些研究将提高我们对粘膜表面先天免疫反应促进持久免疫的机制的理解，并可能为改进目前的霍乱疫苗提供新的策略。

DESCRIPTION (provided by applicant): Cholera remains an important cause of diarrheal illness, as evidenced by its recent emergence in post- earthquake Haiti. Scientific and policy leaders are increasingly calling for the use of preventive strategies such as vaccination for diarrheal diseases like cholera, but current cholera vaccines suffer from immunologic limitations. Most importantly, oral cholera vaccines elicit protection of short duration -- in contrast to naturl infection with V. cholerae, which induces long-lasting immunity. In the research proposed here, we seek to identify the earliest differences in the innate and B cell immune responses after natural infection versus cholera vaccination. We also aim to identify which of these early differences are most critical for the subsequent development of long term immunologic memory. Understanding these early differences may explain why only natural infection with V. cholerae gives rise to long term memory B cell responses which are important for protection against cholera. Because V. cholerae is a human-restricted pathogen, clinical studies are essential to address this question. We propose to draw upon existing collaborations between the Massachusetts General Hospital/Harvard Medical School (MGH/HMS), the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), the Emory Vaccine Center, and the Broad Institute of MIT/Harvard University to address this question in humans. Specifically, we will compare the activation of innate immune responses in mucosal tissue after cholera infection versus vaccination, and we will evaluate which of these differences correlate with long term memory B cell responses in cholera patients. We will also compare antibody secreting cell (ASC) responses in patients and vaccinees. Cloning of immunoglobulin genes and the production of these cloned antibodies from individual ASCs may improve our understanding of differences in the B cell responses between cholera patients and vaccine recipients, and the resulting antibodies may also provide tools with diagnostic and therapeutic potential. These studies will improve our understanding of the mechanisms through which innate immune responses at the mucosal surface foster long-lasting immunity and may point to novel strategies for improving upon current cholera vaccines.