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独特的生理学在它们发挥作用的能力中所起的作用 作为疾病的宿主，这些疾病可能会传染给人类。该项目将在现场条件下进行 在乌干达，研究了三种蝙蝠，它们与埃博拉病毒(EBOV)向人类的传播有不同的联系。通过 通过比较这三种蝙蝠应对类似埃博拉病毒的免疫挑战的能力，这项工作将 帮助确定导致溢出风险的特征。从长远来看，这项工作将有助于识别主机 EBOV和其他对人类构成风险的相关病毒的物种。它还将有助于解释如何不同 不同种类的蝙蝠对不同类型的病毒感染做出反应。该项目的主要重点将是确定 使水库宿主能够耐受感染的行为和分子途径，提供了关键的见解 进入导致溢出的机制之一。这项工作是由一些蝙蝠物种的假设推动的 与特定类型的病毒感染共同进化，因此调整了机制，将 感染期间的病理学。蝙蝠是全球生物多样性的物种，具有许多独特的生态和生理特征 适应能力，包括飞行和使用低温和高温体温的能力 监管。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，并且它们有不同的共同进化历史 病毒病原体；这三个物种中有两个与EBOV流行病学有重大联系。本项目致力于 这些问题在野外自然条件下采取了使用EBOV类病毒的创新方法 颗粒作为实验感染生物危险病原体的代理。这个项目有三个具体的 将使其目标得以实现的目标。首先，该项目测试了特定的非洲蝙蝠 物种将显示EBOV疾病耐受性的特征，以响应EBOV类病毒的挑战 颗粒，因此很可能是天然的水库宿主。这些实验将为我们提供对 蝙蝠的疾病耐受性和EBOV储蓄者的潜在身份(S)。其次，该项目测试 蝙蝠表现出不同水平的疾病耐受性取决于先天免疫途径的假说 在蝙蝠身上经历了独特的进化选择。第三，这个项目探讨了是否容忍 蝙蝠独特的新陈代谢行为促进了对病毒感染的抵抗力，即它们可以 抑制新陈代谢，进入麻木状态，以保存能量，提高新陈代谢，从而提高体温 在飞行过程中。体温变化的作用还知之甚少，这些实验将确定 这些生理反应是否有助于免疫耐受和抵抗 疾病蓄水池。总之，成功完成这些目标将有助于确定感染 耐受性赋予非洲蝙蝠物种作为强毒人畜共患病病毒和 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.