Innate and early B cell responses to V. cholerae

对霍乱弧菌的先天和早期 B 细胞反应

• 批准号: 8630383
• 负责人: JASON B HARRIS
• 金额: $ 82.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630383
• 关键词: Address; Affinity; Antibodies; Antigens; B-Cell Activation; B-Lymphocytes; Bangladesh; Biopsy; Blood Circulation; Cells; Characteristics; Cholera; Cholera Vaccine; Clinical Research; Cloning; Collaborations; Data; Dendritic Cells; Developing Countries; Development; Diagnostic; Disease; Earthquakes; Epidemic; Evaluation; Event; Fostering; General Hospitals; Generations; Genes; Haiti; Homing; Human; Immune; Immune response; Immunity; Immunoglobulin Genes; Immunoglobulin Isotypes; Immunoglobulin Light Chain Genes; Immunoglobulin-Secreting Cells; Immunologic Memory; Immunologics; Individual; Infection; Institutes; Intestines; Kinetics; Life; Massachusetts; Measures; Memory B-Lymphocyte; Mucosal Immune Responses; Mucous Membrane; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Plasma Cells; Plasmablast; Policies; Population; Prevention strategy; Production; Research; Signal Pathway; Somatic Mutation; Sorting - Cell Movement; Specificity; Surface; Systems Biology; Therapeutic; Tissues; Universities; Vaccination; Vaccines; Vibrio cholerae; Work; bactericide; human monoclonal antibodies; improved; innovation; international center; killings; long term memory; medical schools; novel; novel strategies; oral vaccine; pathogen; peripheral blood; public health relevance; response; tool; volunteer

PROJECT SUMMARY 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 natural 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.

项目摘要 霍乱仍然是腹泻病的重要原因，这是其最近出现在 海地地震。科学和政策领导人越来越多地呼吁使用预防策略 作为诸如霍乱之类的腹泻疾病的疫苗接种，但是当前的霍乱疫苗患有免疫学 限制。最重要的是，口服霍乱疫苗可以保护短持续时间 - 与自然相反 霍乱五和霍乱的感染，可诱导长期的免疫力。 在这里提出的研究中，我们试图确定先天和B细胞中最早的差异 自然感染与霍乱疫苗接种后的免疫反应。我们还旨在确定其中哪些 早期差异对于随后的长期免疫记忆的发展至关重要。 了解这些早期差异可以解释为什么只有霍乱弧菌的自然感染会产生 长期记忆B细胞响应对于保护霍乱很重要。 因为霍乱谷是一种人限制的病原体，所以临床研究对于解决这个问题至关重要 问题。我们建议借鉴马萨诸塞州一般之间的现有合作 国际腹泻病研究中心医院/哈佛医学院（MGH/HMS）， 孟加拉国（ICDDR，B），埃默里疫苗中心和麻省理工学院/哈佛大学的广泛研究所 在人类中解决这个问题。具体而言，我们将比较先天免疫反应的激活 霍乱感染与疫苗接种后的粘膜组织，我们将评估其中哪些差异 与霍乱患者的长期记忆B细胞反应相关。我们还将比较抗体分泌 患者和疫苗的细胞（ASC）反应。免疫球蛋白基因的克隆和这些基因的产生 来自单个ASC的克隆抗体可能会提高我们对B细胞反应差异的理解 在霍乱患者和疫苗接收者之间，以及由此产生的抗体也可能提供工具 诊断和治疗潜力。这些研究将提高我们对机制的理解 粘膜表面的先天免疫反应促进了长期的免疫力，并可能指向新颖 改善当前霍乱疫苗的策略。