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

项目总结 阿雷纳病毒是一类人畜共患的rna病毒，可引起严重的出血热疾病。 在人类身上。拉萨病毒(LASV)，一种东半球阿雷纳病毒，流行于西非地区，包括 在塞拉利昂，是拉沙热(LF)的病原体，每年导致数千人死亡。天敌病毒 在过去的几十年里多次进入人类，并出现了已知的变种 禽流感病毒通常表现出更高的人际传播力和更广泛的地理范围。为了这些 原因，疾控中心和世卫组织已将几种人类禽流感病毒列为高度优先病原体， 预测联盟将LASV列为其潜在大流行病原体观察名单上风险最高的病毒。 对抗禽流感病毒的疫苗和疗法是迫切需要的，然而，我们必须首先获得更深层次的 理解产生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的目标，这个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，用于定义基因、功能和 具有广泛特异性的抗LASV抗体的结构特性。我们有 组建了一个协作性、多学科的调查小组，具有长期的富有成效的合作历史 在病毒免疫学方面，与专业知识互补的领域。此外，我们还可以接触到一个单独的队列 位于塞拉利昂的凯内马政府医院是左联阵线的心脏地带 区域。我们希望我们的工作将导致数千种新的抗LASV抗体的发现，表征 这将揭示病毒脆弱性的保守部位，并揭示病毒的确切分子机制 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阿拉伯病毒之间的关系，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.