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：
9107111
负责人：
GRAHAM SIMMONS
金额：
$ 33.41万
依托单位：
VITALANT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107111
关键词：
Acute Address Alphavirus Alphavirus Infections Americas 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 Chikungunya virus Chronic Cloning 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 Immunity In Vitro Individual Infection Lead Licensing Light Luciferases Maps Mediating Membrane Memory B-Lymphocyte Monoclonal Antibodies Mutagenesis Mutation Nature Newborn Infant Patients Phenotype Plasmablast Population Populations at Risk Production Public Health Recovery Reporter Serum Staging Structure Surface Technology Therapeutic United States Vaccines Variant Viral Viral Antigens Virion Virus Virus Assembly Virus Diseases Vulnerable Populations West Nile virus deep sequencing genetic evolution human monoclonal antibodies in vivo neutralizing antibody novel particle pressure prevent prophylactic public health relevance response screening surveillance study vaccine development vector mosquito viral transmission 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, first in the Caribbean and then into the mainland Americas. CHIKV causes extensive human and economic damage, partially due to acute fever and arthralgia, but primarily because of 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 (IRCTM) 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（由适用提供）：如果将其引入美国，则可能会在加勒比海地区，然后在加勒比海，然后进入大陆美洲，可能会引入美国。 CHIKV造成了广泛的人类和经济损害，部分原因是急性热和关节痛，但主要是由于病毒后慢性关节疼痛/关节炎。目前，CHIKV尚无许可的治疗治疗或疫苗。我们将通过识别主要候选候选单克隆抗体（MAB）来开发能够在预防和治疗上使用的治疗方法来解决CHIKV构成的重要公共卫生威胁。重要的是，我们已经证明了针对CHIKV阻止病毒组装/发芽的单克隆动物的能力 - 可能是通过防止形成颗粒所需的包膜糖蛋白驱动的膜曲率的能力。我们将表征针对这种机制的新抗体，并描述全部B细胞曲目，以应对感染 - 既包括急性感染的患者又是康复的个体。最后，我们将表征CHIKV遗传多样性和进化，重点是检测B细胞表位选择的变化和选择。为了实现这些目标，我们将执行三个特定的目的：目标1。对能够发芽抑制的潜在人类单克隆人的识别和表征。我们将从恢复的CHIKV患者中得出并筛选B细胞克隆，专门抑制Chikv病毒释放/发芽。由此产生的mAb将用于体外和体内效力，并使用逃生突变体和诱变来映射它们的表位。 AIM 2。表征急性和记忆B细胞对Chikv感染的反应。使用免疫曲目捕获（IRCTM）技术，我们将在CHIKV感染期间完全绘制B细胞曲目。通过寻找多个个体B细胞占地的收敛演化，可以识别出常见的表位，而进入神经化和萌芽抑制之间的关系将会以急性感染和回收的个体为特征。目标3。chikv包膜糖蛋白多样性和进化的表征。为了评估目标1和2中得出的抗体的潜力，我们将表征ChiKV包膜序列序列变化的性质和程度，该病毒分离株从研究中（超过三年）与CHIKV序列一起从更广泛的全球人群中获得的病毒分离株变化。将筛选数据集的选择性压力签名，尤其是从体液响应中。总而言之，我们希望开发出新颖的mAB，以针对病毒生命周期的特定阶段。感染过程中的体液反应将被映射，并与病毒多样性和进化有关。