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

病原体的跨物种传播是对全世界公共卫生的主要威胁， 占人类新发传染病的75%。蝙蝠作为无症状的水库 许多人畜共患病病毒的宿主，这些病毒在人类中是致命的，没有疫苗或 存在特定的治疗方法，表明翼手目免疫系统可以控制这些 病毒虽然最近人们对蝙蝠先天的特性越来越感兴趣， 免疫力，他们的体液免疫反应仍然在分子水平上未被探索，尽管它 已知参与对抗病原体。先前的研究显示蝙蝠B细胞异常快速 与其他哺乳动物相比， 多样性，这表明这些哺乳动物成功科普惊人的 病毒的多样性。我们认为蝙蝠与病毒的长期共同进化可能导致了 高度特异性免疫球蛋白可变重链片段的存在在 成功地控制病原体和蝙蝠抗体代表了一个未开发的病毒来源， 抑制剂的该项目将阐明蝙蝠体液免疫在控制 病原体感染，确定针对人畜共患病病毒的新疗法，并指导 下一代病毒进入蛋白质抑制剂的计算机设计。这项工作将产生 防治新出现和重新出现的人畜共患病病毒的工具，包括一些 尚未出现或被发现，将是协助大流行防范工作的关键。

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.