Defining Molecular Epitopes of Protective Antibodies to Flaviviruses

定义黄病毒保护性抗体的分子表位

• 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
• 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

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.

项目概要/摘要： 本K 08指导临床科学家职业奖申请的目的是为Alena Markmann博士提供 在人类免疫学和研究人类免疫细胞的最新方法方面有着坚实的基础， 开始了她的独立研究生涯，研究人类对RNA病毒的免疫反应。马克曼博士是 北卡罗来纳州-查佩尔山（查珀尔山）学校医学助理教授，终身教职 医学与微生物学和免疫学系的联合任命。这位候选人有 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知识， 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 对登革热和寨卡等新出现的黄病毒的免疫反应可以抑制病毒感染和疾病， 增强病毒复制并加重疾病。候选人和她的导师Aravinda de Silva博士 我设计了一个培训计划，其中包括严格的研究组成部分，沿着教学指导，网络 和演讲机会，团队管理技能，以及手稿写作和granulate。 这些技能将共同建立成功的职业发展所需的方法和原则。 黄病毒是一种有包膜的正链RNA病毒，对人类构成日益严重的威胁 每年造成数百万人感染它们是病媒传播的，由蜱和蚊子传播， 一系列疾病表现，包括发热性疾病、可导致终身 并发症、先天性寨卡综合征和登革出血热和休克综合征。在大多 部分黄病毒感染导致针对感染病毒的中和保护性抗体应答， 感染后持续数年。然而，这四种登革热病毒在抗原性上非常相似，在许多情况下， 导致产生对个体具有的登革热病毒血清型的广泛交叉中和抗体应答， 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， 血清中的抗体此外，尽管我们知道寨卡病毒保护的几个主要目标， 由于研究了记忆B细胞的抗体反应，我们不知道血清靶点是什么。初步结果 这表明，在寨卡血清抗体反应的情况下，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，我们假设在目标1中， 应答将反映记忆B细胞应答，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较少。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导致识别关键的保护性 病毒从血清抗体区室靶向登革热和寨卡病毒，以告知成功的 疫苗设计