Tolerance and resistance responses of African bats to viral antigens: Immunological tradeoffs in zoonotic reservoir hosts.

摘要 这个项目的重点是了解蝙蝠的独特生理学在其作为一个生物体的能力中所起的作用。 是传染给人类的疾病的宿主该项目将在野外条件下进行 在乌干达，三种蝙蝠与埃博拉病毒（EBOV）传播给人类有不同的联系。通过 通过比较这三种蝙蝠对埃博拉样免疫挑战的反应能力，这项工作将 帮助识别导致溢出风险的特征。从长远来看，这项工作将有助于确定主机 EBOV和其他对人类构成风险的相关病毒。这也有助于解释 不同种类的蝙蝠对不同类型的病毒感染有反应。该项目的主要重点将是确定 行为和分子途径，使水库主机容忍感染，提供关键的见解， 成为导致溢出的机制之一。这项工作是由一个假设驱动的，即一些蝙蝠物种 与特定类型的病毒感染共同进化，因此，有适应机制， 感染期间的病理学蝙蝠是全球生物多样性和许多独特的生态和生理 适应，包括飞行和利用体温过低和过高的能力 调控这个项目的重点是三种蝙蝠，因为它们与人类有密切的接触， 它们的栖息地覆盖了EBOV暴露风险的范围，它们有不同的共同进化历史， 病毒病原体;三个物种中的两个与EBOV流行病学有重要联系。该项目涉及 这些问题在自然条件下的领域，通过采取创新的方法，使用EBOV病毒样 颗粒作为生物危害性病原体实验感染的代表。该项目有三个具体 这将有助于实现其目标。首先，该项目测试了一个假设，即特定的非洲蝙蝠 物种将显示EBOV疾病耐受性的特征，以响应EBOV病毒样抗原的攻击。 颗粒，因此很可能是天然的储库宿主。这些实验将提供重要的洞察力， 蝙蝠的疾病耐受性和EBOV宿主的潜在身份。其次，该项目测试了 蝙蝠表现出依赖于先天免疫途径的不同水平的疾病耐受性的假说 经历了蝙蝠独特的进化选择。第三，这个项目探讨是否容忍 和抵抗病毒感染的能力是由蝙蝠独特的代谢行为促进的，即它们可以 抑制新陈代谢，进入休眠状态，以保存能量，并能提高新陈代谢，从而提高体温 在飞行中。人们对体温变化的作用知之甚少，这些实验将确定 这些生理反应是否有助于免疫耐受性和抗性， 病源总之，这些目标的成功完成将有助于确定是否感染 耐受性赋予非洲蝙蝠物种作为有毒的人畜共患病病毒的储存宿主的能力， 将确定有助于耐受表型的分子、生理和行为机制。

ABSTRACT This project focuses on understanding the role that the unique physiology of bats plays in their ability to act as host reservoirs for diseases that can spill over to humans. The project will be carried out under field conditions in Uganda on three species of bats that have varying links to the spread of Ebola virus (EBOV) to humans. By comparing the ability of these three species of bats to respond to Ebola-like immune challenges, this work will help identify the characteristics that contribute to spillover risk. In the long term, this work will help identify host species for EBOV and other related viruses that present risk to humans. It will also help explain how different species of bats respond to different types of viral infections. The main focus of this project will be to identify behaviors and molecular pathways that enable reservoir hosts to tolerate infections, providing critical insight into one of the mechanisms that leads to spillover. This work is driven by the hypothesis that some bat species have coevolved with particular types of viral infections and, therefore, have adapted mechanisms to minimize pathology during infection. Bats are globally biodiverse and have many unique ecological and physiological adaptations, including flight and the ability to employ both hypo- and hyperthermic body temperature regulation. This project focuses on three bat species chosen because they are in close contact with humans, their habitats cover the range of EBOV exposure risk, and they have divergent coevolutionary histories with viral pathogens; two of the three species have significant ties to EBOV epidemiology. This project addresses these questions under natural conditions in the field by taking the innovative approach of using EBOV virus-like particles as a proxy for experimental infection with biohazardous pathogens. This project has three specific aims that will allow the achievement of its goals. First, the project tests the hypothesis that specific African bat species will display signatures of EBOV disease tolerance in response to challenge with EBOV virus-like particles, and thus are likely to be natural reservoir hosts. These experiments will provide significant insight into disease tolerance in bats and the potential identity of EBOV reservoir(s). Second, this project tests the hypothesis that bats display variable levels of disease tolerance that depend upon innate immune pathways that have undergone unique evolutionary selection in bats. Third, this project explores whether tolerance of and resistance to viral infection are facilitated by the unique metabolic behaviors of bats, namely that they can depress metabolism and enter torpor to conserve energy and can elevate metabolism and thus temperature during flight. The role of changes in body temperature is poorly understood and these experiments will identify whether these physiological responses contribute to immunological tolerance and resistance in important disease reservoirs. Together, the successful completion of these goals will help determine whether infection tolerance confers on African bat species the ability to serve as reservoir hosts for virulent zoonotic viruses and will identify molecular, physiological, and behavioral mechanisms that contribute to tolerance phenotypes.