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.

项目总结