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: 10688292
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 87.03万
• 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/10688292
• 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; Categories; Cells; Cessation of life; Classification; Clinical; Clonal Expansion; 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; Hospitalization; 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; Productivity; Property; RNA Viruses; Recording of previous events; Research Personnel; Resolution; Risk; 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; cohort; design; effective therapy; genetic analysis; high risk; immunogenic; innovation; interest; long-term sequelae; member; multidisciplinary; multiple omics; neutralizing antibody; novel; pandemic pathogen; pandemic potential; pathogen; priority pathogen; response; segregation; 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.

项目概要 沙粒病毒是人畜共患 RNA 病毒家族，能够引起严重的出血热疾病 在人类中。拉沙病毒（LASV），一种旧世界沙粒病毒，在西非地区流行，包括 塞拉利昂是拉沙热 (LF) 的病原体，每年导致数千人死亡。沙粒病毒 在过去的几十年里，这种病毒反复进入人类体内，并且已知的新变种不断出现 沙粒病毒通常表现出更高的人际传播性和更广泛的地理范围。对于这些 由于这些原因，美国疾病控制和预防中心 (CDC) 和世界卫生组织 (WHO) 将几种人类沙粒病毒列为高度优先病原体， PREDICT 联盟将 LASV 列为其潜在大流行病原体观察名单中风险最高的病毒。 迫切需要针对沙粒病毒的疫苗和治疗方法，但是，我们必须首先获得更深入的了解 了解导致保护性体液免疫的分子机制。虽然发现 有效的临床对策是最终目标，该合作项目的重点是利用 创新的高通量抗体发现和表征工具，用于定义遗传、功能和 抗 LASV 抗体的结构特性，对人类沙粒病毒具有广泛的特异性。我们有 组建了一个协作的、多学科的研究小组，具有悠久的富有成效的合作历史 病毒免疫学和互补的专业领域。此外，我们还可以接触到一个单一的群体 凯内马政府医院的 LF 幸存者，该医院位于塞拉利昂，是 LF 的中心 区。我们预计我们的工作将导致发现数​​千种新型抗 LASV 抗体、表征 其中将揭示病毒脆弱性的保守位点并揭示病毒的精确分子机制 中和。这些基础研究直接解决了我们对相互作用的理解中的关键差距 体液免疫和引起出血热的沙粒病毒之间的关系，并将作为未来的基础 转化研究。

项目成果

A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection.

• DOI: 10.1038/s41467-023-41376-6
• 发表时间: 2023-09-12
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ronk, Adam J.;Lloyd, Nicole M.;Zhang, Min;Atyeo, Caroline;Perrett, Hailee R.;Mire, Chad E.;Hastie, Kathryn M.;Sanders, Rogier W.;Brouwer, Philip J. M.;Saphire, Erica Olmann;Ward, Andrew B.;Ksiazek, Thomas G.;Alvarez Moreno, Juan Carlos;Thaker, Harshwardhan M.;Alter, Galit;Himansu, Sunny;Carfi, Andrea;Bukreyev, Alexander
• 通讯作者: Bukreyev, Alexander