Defining Molecular Epitopes of Protective Antibodies to Flaviviruses

定义黄病毒保护性抗体的分子表位

基本信息

批准号：
10560612
负责人：
Alena Janda Markmann
金额：
$ 19.52万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560612
关键词：
Acute Adult Affect Antibodies Antibody Response Antibody-mediated protection Antigens Applications Grants Appointment Area Award B-Lymphocytes Binding Binding Sites Biological Assay Bone Marrow Cell Separation Cells Cellular Assay Child Clinical Clone Cells Cross Reactions Culicidae Dengue Dengue Hemorrhagic Fever Dengue Infection Dengue Virus Development Disease E protein Epidemiology Epitopes Exposure to Fever Flavivirus Foundations Hemorrhagic Shock Human Immune Immune response Immunity Immunoglobulin G Immunoglobulin Somatic Hypermutation Immunology Individual Infection Instruction Investigation Ions Japanese encephalitis virus Joints Knowledge Latin America Life Manuscripts Maps Marrow Medicine Memory B-Lymphocyte Mentors Methods Microbiology Molecular Monoclonal Antibodies Morbidity - disease rate North Carolina Pathogenicity Peptides Plasma Plasma Cells Polysaccharides Population Proteins Proteomics Publications RNA Viruses Recombinants Research Resolution Role Scientist Serology Serotyping Serum Site Structure Syndrome Technology Tertiary Protein Structure Therapeutic Time Training United States National Institutes of Health Universities Vaccine Design Viral Viral Hemorrhagic Fevers Virus Virus Diseases Virus Replication West Nile Work Writing Yellow Fever ZIKA ZIKV infection Zika Virus adaptive immune response adaptive immunity career career development complementarity-determining region 3 congenital zika syndrome convalescent plasma cross reactivity design design and construction dimer epidemic virus experience experimental study glycosylation high resolution imaging improved medical schools neutralizing antibody neutralizing monoclonal antibodies new technology novel polyclonal antibody professor recombinant virus response screening secondary infection skills tenure track tick transmission tool transmission process vector mosquito vector-borne virus development

项目摘要

Project Summary/Abstract: The objective of this K08 Mentored Clinical Scientist Career Award Application is to provide Dr. Alena Markmann with a strong foundation in human immunology and the latest methods for studying human immune cells before launching her independent research career on the human immune response to RNA viruses. Dr. Markmann is an Assistant Professor of Medicine, tenure track, at the University of North Carolina -Chapel Hill (UNC) School of Medicine with a joint appointment in the Department of Microbiology and Immunology. The candidate has expertise in and a strong track record of publications on antibody structure, antibody-antigen interactions and antibody neutralization of viruses. By strengthening her knowledge of adaptive immunity to RNA viruses and mastering the latest methods for analyzing antigen specific B cells, Dr. Markmann will study how the human immune response to emerging flaviviruses like dengue and Zika can suppress viral infection and disease or enhance viral replication and exacerbate disease. The candidate and her mentor Dr. Aravinda de Silva have designed a training plan that includes a rigorous research component along with didactic instruction, networking and presentation opportunities, team management skills as well as manuscript writing and grantsmanship. Together these skills will establish the methods and principles necessary for successful career development. Flaviviruses are enveloped positive stranded RNA viruses that pose a growing threat to the human population and cause millions of infections annually. They are vector-borne, transmitted by ticks and mosquitoes, and cause a spectrum of disease manifestations including febrile illness, encephalitides that can cause lifelong complications, Congenital Zika Syndrome and dengue hemorrhagic fever and shock syndromes. For the most part, flaviviral infection result in a neutralizing protective antibody response against the infecting virus, that can last for years after infection. The four dengue viruses however are very similar antigenically and in many cases, result in generating a broad cross-neutralizing antibody responseto dengue virus serotypes that individuals have not yet been exposed to. Thus far, no one has identified the viral target site of these broadly neutralizing dengue antibodies that exist in the serum. Furthermore, though we know of a few major targets of the Zika protective antibody response from studying memory B cells, we do not know what the serum targets are. Preliminary results suggest that in the case of Zika serum antibody responses, binding targets are correlated with known strongly neutralizing memory B cell-derived antibody targets. Thus, we hypothesize in Aim 1, that serum antibody responses will mirror memory B cell responses, but will likely come from a smaller number of B cell clones and be less cross-reactive with other flaviviruses. In Aim 2 we will identify the viral binding targets of broadly cross- neutralizing dengue antibodies from the serum. These studies will result in the ident ification of critical protective viral targets to both dengue and Zika viruses from the serum antibody compartment in order to inform successful vaccine design.

项目摘要/摘要：此 K08 指导临床科学家职业奖申请的目的是为 Alena Markmann 博士提供拥有深厚的人体免疫学基础和研究人体免疫细胞的最新方法开启了她对 RNA 病毒的人类免疫反应的独立研究生涯。马克曼博士是北卡罗来纳大学教堂山分校 (UNC) 学院终身教授医学助理教授医学博士，并在微生物学和免疫学系联合任命。候选人有在抗体结构、抗体-抗原相互作用和抗体中和病毒。通过加强她对 RNA 病毒的适应性免疫的了解，掌握了分析抗原特异性 B 细胞的最新方法，Markmann 博士将研究人类如何对登革热和寨卡病毒等新兴黄病毒的免疫反应可以抑制病毒感染和疾病或增强病毒复制并加剧疾病。候选人和她的导师 Aravinda de Silva 博士设计了一个培训计划，其中包括严格的研究部分以及教学指导、网络和演讲机会、团队管理技能以及手稿写作和资助。这些技能将共同建立成功职业发展所需的方法和原则。黄病毒是有包膜的正链 RNA 病毒，对人类构成越来越大的威胁并每年造成数以百万计的感染。它们是媒介传播的，通过蜱虫和蚊子传播，并导致一系列疾病表现，包括发热性疾病、可导致终生的脑炎并发症、先天性寨卡综合症、登革出血热和休克综合症。对于大多数部分，黄病毒感染会导致针对感染病毒的中和保护性抗体反应，这可以感染后持续数年。然而，四种登革热病毒在抗原上非常相似，并且在许多情况下，导致对个体所具有的登革热病毒血清型产生广泛的交叉中和抗体反应还没有接触过。到目前为止，还没有人确定这些广泛中和登革热的病毒靶位点血清中存在的抗体。此外，尽管我们知道寨卡病毒防护的几个主要目标研究记忆 B 细胞产生的抗体反应，我们不知道血清靶标是什么。初步结果表明就寨卡病毒血清抗体反应而言，结合靶点与已知的强烈相关中和记忆 B 细胞衍生的抗体靶标。因此，我们在目标 1 中假设，血清抗体反应将反映记忆 B 细胞反应，但可能来自较少数量的 B 细胞克隆与其他黄病毒的交叉反应性较小。在目标 2 中，我们将确定广泛交叉的病毒结合靶点。中和血清中的登革热抗体。这些研究将确定关键的保护措施病毒从血清抗体区室靶向登革热和寨卡病毒，以告知成功疫苗设计。