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球公共健康的主要威胁， 占人类新发传染病的75%。蝙蝠充当无症状的储蓄者 许多人畜共患病毒的宿主，这些病毒对人类是致命的，没有疫苗或 存在特定的治疗方法，表明翼手龙的免疫系统可以控制这些 病毒。尽管最近人们对蝙蝠与生俱来的特性越来越感兴趣 免疫，它们的体液免疫反应仍未在分子水平上被探索，尽管它 已知参与抗击病原体。先前的研究显示蝙蝠B细胞速度异常快 增殖，与其他哺乳动物相比，和一种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应对令人震惊的 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 高度特异的免疫球蛋白可变重链片段的存在在 成功地控制了病原体，蝙蝠抗体代表了一种尚未开发的病毒来源 抑制剂。拟议的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毒的新疗法，并指导 病毒进入的下一代蛋白质抑制剂的计算设计。这项工作将产生 对抗新出现和重新出现的人畜共患病病毒的工具，包括一些已经 尚未出现或被发现，并将是协助大流行防备工作的关键。

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.