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

项目摘要 沙粒病毒是一种能引起严重出血热的人畜共患RNA病毒 在人类身上。拉沙病毒（LASV），一种旧大陆沙粒病毒，在西非地区流行，包括 塞拉利昂是拉沙热（LF）的病原体，每年造成数千人死亡。沙粒病毒 在过去的几十年里，这种病毒多次进入人类， 沙粒病毒通常显示出增加的人传人性和更广的地理范围。为这些 出于各种原因，CDC和WHO已将几种人类沙粒病毒列为高优先级病原体， PREDICT联合会将LASV列为其潜在大流行病原体观察名单上风险最高的病毒。 迫切需要针对沙粒病毒的疫苗和治疗方法，然而，我们必须首先获得更深入的研究， 了解导致保护性体液免疫的分子机制。尽管这一发现 有效的临床对策是最终目标，这个合作项目的重点是利用 创新的，高通量的抗体发现和表征工具，以确定遗传，功能和 抗LASV抗体在人沙粒病毒中具有广泛特异性的结构特性。我们有 组建了一个具有长期合作历史的多学科合作研究小组 在病毒免疫学和互补领域的专业知识。另外，我们还能接触到 塞拉利昂凯内马政府医院是解放阵线的中心， 区我们希望我们的工作将导致发现数千种新的抗LASV抗体， 这些研究将揭示病毒脆弱性的保守位点，并揭示病毒感染的精确分子机制。 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 翻译研究

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.