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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.