Unraveling the bat humoral immune response against zoonotic viruses to guide the design of next-generation therapeutics

揭示蝙蝠针对人畜共患病毒的体液免疫反应，以指导下一代疗法的设计

基本信息

批准号：
10462736
负责人：
David Veesler
金额：
$ 108.85万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-07-31
项目状态：
未结题

项目摘要

Cross-species transmission of pathogens is a major threat to public health worldwide and accounts for 75% of emerging human infectious diseases. Bats act as asymptomatic reservoir hosts for numerous zoonotic viruses, that are lethal in humans and for which no vaccines or specific therapeutics exist, indicating that the chiropteran immune system can control these viruses. Although there has been a recent growing interest in the peculiarities of bat innate immunity, their humoral immune response remains unexplored at the molecular level despite its known participation to fighting off pathogens. Previous studies revealed unusually fast bat B cell proliferation, compared to other mammals, and an exceptional immunoglobulin combinatorial diversity, suggesting a possible way these mammals successfully cope with an astounding diversity of viruses. We propose that the long co-evolution of bats with viruses could have led to the presence of highly specific immunoglobulin variable heavy chain segments playing a role in successfully controlling pathogens and that bat antibodies represent an untapped source of viral inhibitors. The proposed project will illuminate the role of bat humoral immunity in controlling pathogen infections, identify novel therapeutics against zoonotic viruses and guide the computational design of next-generation protein inhibitors of viral entry. This work will generate tools to combat emerging and re-emerging zoonotic viruses, including some pathogens that have not yet emerged or been discovered, and will be key to assist pandemic preparedness effort.

病原体的跨物种传播是全球公共卫生的主要威胁占新兴人类传染病的75％。蝙蝠充当无症状的储层许多人畜共患病毒的宿主，在人类中致命，没有疫苗或存在特定的治疗剂，表明手柄免疫系统可以控制这些病毒。尽管最近对蝙蝠先天的特殊性越来越兴趣免疫力，尽管其体液免疫反应仍未在分子水平上探索已知参与与病原体作斗争。先前的研究显示出异常快速的BAT B细胞与其他哺乳动物相比，增殖和特殊的免疫球蛋白组合多样性，这表明了这些哺乳动物成功地应对惊人的方式病毒的多样性。我们建议，蝙蝠与病毒的长期共同进化可能导致高度特定的免疫球蛋白可变重链节段的存在在成功控制病原体和蝙蝠抗体代表了未开发的病毒来源抑制剂。拟议的项目将阐明蝙蝠的体液免疫在控制中的作用病原体感染，鉴定针对人畜共患病毒的新型治疗剂，并指导病毒进入的下一代蛋白抑制剂的计算设计。这项工作将产生打击新兴和重新出现的人畜共患病毒的工具，包括一些具有的病原体尚未出现或被发现，这将是协助大流行准备工作的关键。