Protective B-cell responses in chikungunya virus infection

基孔肯雅病毒感染中的保护性 B 细胞反应

基本信息

批准号：
9117149
负责人：
GRAHAM SIMMONS
金额：
$ 43.64万
依托单位：
VITALANT
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-19 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117149
关键词：
Acute Address Alphavirus Alphavirus Infections Animal Model Antibodies Antibody Binding Sites Antigens Arboviruses Area Arthralgia Arthritis B cell repertoire B-Lymphocyte Epitopes B-Lymphocytes Bar Codes Binding Biological Assay Caribbean region Cell Separation Cells Central America Chikungunya virus Chronic Common Epitope Data Set Development Disease Disease Outbreaks Economics Enrollment Enzyme-Linked Immunosorbent Assay Epidemic Epitopes Escape Mutant Event Evolution Fever Genbank Generations Genes Genetic Variation Glycoproteins Goals Health Human Immune In Vitro Individual Infection Lead Licensing Light Luciferases Maps Mediating Membrane Memory B-Lymphocyte Monoclonal Antibodies Mutagenesis Mutation Nature Patients Phenotype Plasmablast Population Production Public Health Recovery Reporter Serum South America Staging Structure Surface Technology Therapeutic United States Vaccines Variant Viral Viral Antigens Virion Virus Virus Diseases West Nile virus deep sequencing genetic evolution human monoclonal antibodies in vivo neutralizing antibody novel particle pressure prevent prophylactic response screening surveillance study transmission process vaccine development vector mosquito virus envelope virus genetics

项目摘要

DESCRIPTION (provided by applicant): Chikungunya virus (CHIKV) has the potential to create a major public health impact should it be introduced into the United States, as seems likely following a large and sustained outbreak in the Caribbean. CHIKV causes extensive human and economic damage, primarily due to acute fever and arthralgia and post-viral chronic joint pain/arthritis. Currently no licensed therapeutic treatments or vaccines exist for CHIKV. We will address the important public health threat posed by CHIKV by identifying lead candidate monoclonal antibodies (mAbs) for development into treatments capable of being used both prophylactically and therapeutically. Importantly, we have demonstrated the ability of mAbs directed against CHIKV to block viral assembly/budding - probably by preventing the envelope glycoprotein-driven membrane curvature required to form particles. We will characterize new antibodies targeting this mechanism, as well as describe the full B-cell repertoire in response to infection - both in acutely infected patients and recovered individuals. Finally, we will characterize CHIKV genetic diversity and evolution with emphasis on detecting variation and signatures of selection at B-cell epitopes. In order to achieve these goals we will perform three Specific Aims: Aim 1. Identification and characterization of potent human monoclonals capable of budding inhibition. We will derive and screen B-cell clones from recovered CHIKV patients specifically for inhibition of CHIKV virus release/budding. Resulting mAbs will be characterized for in vitro and in vivo potency, and their epitopes will be mapped using escape mutants and mutagenesis. Aim 2. Characterize acute and memory B-cell responses to CHIKV infection. Using immune repertoire capture (IRC) technology, we will fully map B-cell repertoires during CHIKV infection. Common epitopes will be identified by looking for convergent evolution of B-cell paratopes in multiple individuals, and the relationship between entry neutralization and budding inhibition will be characterized in acutely infected and recovered individuals. Aim 3. Characterization of CHIKV envelope glycoprotein diversity and evolution. In order to assess the potential for the antibodies derived in Aims 1 and 2 to be broadly cross reactive, we will characterize the nature and extent of CHIKV envelope sequence variation in viral isolates derived from individuals enrolled in the study (over three years) together with CHIKV sequences from the wider global population. Data sets will be screened for signatures of selective pressure, particularly from the humoral response. In summary, we hope to develop novel mAbs, targeting specific stages of the viral lifecycle. The humoral responses during infection will be mapped and related to viral diversity and evolution.

描述（由申请人提供）：基孔肯雅病毒 (CHIKV) 如果传入美国，有可能对公共卫生产生重大影响，在加勒比地区大规模持续爆发 CHIKV 后，它可能会造成广泛的人类和经济损失。损害，主要是由于急性发烧和关节痛以及病毒后慢性关节疼痛/关节炎，目前尚无针对 CHIKV 的许可治疗方法或疫苗。通过识别主要候选单克隆抗体 (mAb) 来开发可用于预防和治疗的治疗方法来抑制 CHIKV 重要的是，我们已经证明了针对 CHIKV 的 mAb 能够阻止病毒组装/出芽 - 可能是通过阻止包膜糖蛋白驱动的。我们将描述针对这种机制的新抗体的特征，并描述对感染做出反应的完整 B 细胞库 - 无论是在急性感染患者还是康复个体中。最后，我们将表征 CHIKV 遗传多样性和进化，重点是检测 B 细胞表位的变异和选择特征。为了实现这些目标，我们将实现三个具体目标：目标 1. 能够鉴定和表征有效的人类单克隆抗体。我们将从康复的 CHIKV 患者中衍生并筛选专门用于抑制 CHIKV 病毒释放/出芽的 B 细胞克隆，并将对所得单克隆抗体进行体外和体内表征。目标 2. 使用免疫组库捕获 (IRC) 技术，表征 CHIKV 感染期间的 B 细胞组库。通过寻找多个个体中 B 细胞互补位的趋同进化来识别共同表位，并在急性感染中表征进入中和和出芽抑制之间的关系目标 3. CHIKV 糖蛋白多样性和进化的表征为了评估目标 1 和 2 中衍生的抗体广泛交叉反应的潜力，我们将表征病毒中 CHIKV 包膜序列变异的性质和程度。来自参加该研究的个体（超过三年）的分离株以及来自更广泛的全球人群的 CHIKV 序列将被筛选以寻找选择性压力的特征，特别是来自体液反应的特征。总之，我们希望。开发针对病毒生命周期特定阶段的新型单克隆抗体，将绘制出感染期间的体液反应并将其与病毒多样性和进化相关联。