Genetic, structural and functional profiling of the human antibody response to arenavirus infection

人类抗体对沙粒病毒感染反应的遗传、结构和功能分析

• 批准号: 10514498
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 88.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514498
• 关键词: Address; Africa; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Area; Arenavirus; Arenavirus Infections; B-Lymphocytes; Basic Science; Binding; Biological Assay; Case Fatality Rates; Case Study; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Collaborations; Complex; Country; Development; Disease; Disease Outbreaks; Ebola; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; FDA approved; Family; Foundations; Future; Genetic; Geographic Distribution; Geography; Ghana; Glycoproteins; Goals; Government; Guinea; Heart; Hospitals; Human; Humoral Immunities; Immune Evasion; Immune response; Immune system; Immunity; Immunogenetics; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunology; Infection; Ivory Coast; Lassa Fever; Lassa virus; Liberia; Mali; Maps; Molecular; Monoclonal Antibodies; Nigeria; Old World Arenaviruses; Pathogenesis; Patients; Phenotype; Phylogenetic Analysis; Population; Property; RNA Viruses; Recording of previous events; Research Personnel; Resolution; Risk; Rivers; Rodent; Serum; Sierra Leone; Site; Specificity; Structure; Surveys; Survivors; Tacaribe Complex Viruses; Techniques; Therapeutic; Togo; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Virus; Vulnerable Populations; Work; Zoonoses; adaptive immunity; base; cohort; design; effective therapy; genetic analysis; high risk; immunogenic; innovation; interest; long-term sequelae; member; multidisciplinary; multiple omics; neutralizing antibody; novel; pandemic disease; pathogen; priority pathogen; response; tool; translational study; transmission process; vaccine development; virus host interaction

PROJECT SUMMARY Arenaviruses are a family of zoonotic RNA viruses that are capable of causing severe hemorrhagic fever disease in humans. Lassa virus (LASV), an Old World arenavirus which is endemic in regions of West Africa including Sierra Leone and is the causative agent of Lassa fever (LF), causes thousands of deaths annually. Arenaviruses have repeatedly crossed over into humans over the past several decades, and emerging variants of known arenaviruses often display increased human-to-human transmissibility and broader geographic range. For these reasons, the CDC and WHO have classified several human arenaviruses as high priority pathogens and the PREDICT consortium ranked LASV as the highest risk virus on their watchlist of potential pandemic pathogens. Vaccines and therapeutics against arenaviruses are urgently needed, however, we must first gain a much deeper understanding of the molecular mechanisms that result in protective humoral immunity. Although the discovery of effective clinical countermeasures is the ultimate goal, this collaborative project focuses on leveraging innovative, high-throughput antibody discovery and characterization tools to define the genetic, functional and structural properties of anti-LASV antibodies with broad specificity across human arenaviruses. We have assembled a collaborative, multidisciplinary group of investigators with a long history of productive collaboration in viral immunology and with complementary areas of expertise. Additionally, we have access to a singular cohort of LF survivors at Kenema Government Hospital, which is located in Sierra Leone and is at the heart of the LF zone. We expect our work will result in the discovery of thousands of novel anti-LASV antibodies, characterization of which will reveal conserved sites of viral vulnerability and uncover the precise molecular mechanisms of viral neutralization. These fundamental studies directly address critical gaps in our understanding of the interplay between humoral immunity and hemorrhagic fever-causing arenaviruses and will serve as a foundation for future translational studies.

项目摘要 体育症病毒是一个人畜共患的RNA病毒家族，能够引起严重的出血热疾病 在人类中。 Lassa病毒（LASV），这是一种旧世界体育馆，在西非地区是特有的 塞拉利昂（Sierra Leone），是Lassa Fever（LF）的病因，每年造成数千人死亡。体育病毒 在过去的几十年中，已经反复跨入人类，并出现了已知的变种 体育症病毒通常表现出增加人类到人类的可传播性和更广泛的地理范围。为此 原因，疾病预防控制中心并将几个人类体育症病毒归类为高优先病原体和 预测财团将LASV排名为其潜在大流行病原体的监视清单中的最高风险病毒。 但是，迫切需要针对竞技病毒的疫苗和治疗剂，但是，我们必须首先获得更深层次的 了解导致保护性体液免疫的分子机制。虽然是发现 有效的临床对策是最终目标，该协作项目着重于利用 创新，高通量抗体发现和表征工具，以定义遗传，功能和功能 抗LASV抗体的结构特性在人类体内病毒中具有广泛特异性。我们有 组建了一个合作，多学科的调查员小组，该小组具有悠久的生产性合作历史 在病毒免疫学和互补领域的专业领域。此外，我们可以访问一个单一的队列 位于塞拉利昂（Sierra Leone）的Kenema政府医院的LF幸存者 区。我们预计我们的工作将导致发现成千上万种新型的抗LASV抗体，表征 其中将揭示病毒脆弱性的保守位点，并发现病毒的精确分子机制 中和。这些基本研究直接解决了我们对相互作用的理解中的关键差距 在体液和出血性发烧的舞台病毒之间，将成为未来的基础 翻译研究。