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: 9185932
• 负责人: JASON B HARRIS
• 金额: $ 75.96万
• 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/9185932
• 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; Duodenum; Earthquakes; Epidemic; Evaluation; Event; Fostering; General Hospitals; Generations; Genes; Genetic Transcription; Haiti; Homing; Human; Immune; Immune response; Immune signaling; Immunity; Immunoglobulin Genes; Immunoglobulin Isotypes; Immunoglobulin Light Chain Genes; Immunoglobulin-Secreting Cells; Immunologic Memory; Immunologics; Individual; Infection; Innate Immune Response; Institutes; Intestines; Kinetics; 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; Specificity; Surface; Systems Biology; Therapeutic; Tissues; Universities; Vaccination; Vaccines; Vibrio cholerae; Work; bactericide; genetic signature; human monoclonal antibodies; improved; innovation; international center; killings; long term memory; medical schools; novel; novel strategies; oral vaccine; pathogen; peripheral blood; predictive signature; public health relevance; response; tool; volunteer

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.

说明(申请人提供)：霍乱仍然是腹泻疾病的一个重要原因，最近在地震后海地出现的霍乱就是明证。科学和政策领导人越来越多地呼吁使用预防策略，如为霍乱等腹泻疾病接种疫苗，但目前的霍乱疫苗存在免疫学限制。最重要的是，口服霍乱疫苗产生的保护作用是短暂的--而自然感染霍乱弧菌则会诱导持久的免疫。在这里提出的研究中，我们试图确定自然感染和霍乱疫苗接种后先天和B细胞免疫反应的最早差异。我们的目标也是确定这些早期差异中的哪些对随后的长期免疫记忆的发展最关键。了解这些早期的差异可能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的病原体，因此必须进行临床研究来解决这个问题。我们建议利用麻省总医院/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/哈佛大学博德研究所之间的现有合作来解决这一人类问题。具体地说，我们将比较霍乱感染和疫苗接种后粘膜组织中天然免疫反应的激活情况，并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。我们还将比较患者和疫苗接种者的抗体分泌细胞(ASC)反应。从单个ASCs中克隆免疫球蛋白基因并产生这些克隆抗体可能会提高我们对霍乱患者和疫苗接受者之间B细胞反应差异的了解，由此产生的抗体也可能提供具有诊断和治疗潜力的工具。这些研究将提高我们对粘膜表面的先天免疫反应促进持久免疫的机制的理解，并可能指出改进当前霍乱疫苗的新策略。