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

非洲蝙蝠对病毒抗原的耐受性和抗性反应：人畜共患病储存宿主的免疫学权衡。

• 批准号: 10210766
• 负责人: Kenneth A Field
• 金额: $ 61.14万
• 依托单位: BUCKNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210766
• 关键词: Achievement; Address; Adjuvant; Africa; African; Antibody Formation; Antiviral Agents; Area; Bacterial Antigens; Behavior; Behavioral Mechanisms; Body Temperature; Characteristics; Chiroptera; Coronavirus; Disease; Disease Reservoirs; Disease model; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Ecology; Epidemiology; Equilibrium; Exhibits; Female; Fever; Filovirus; Goals; Habitats; Human; Immune; Immune Tolerance; Immune response; Immune signaling; Immunologics; Infection; Lead; Learning; Link; Metabolic; Metabolism; Molecular; Paramyxovirus; Pathology; Pathway interactions; Phenotype; Physiologic Thermoregulation; Physiological; Physiological Adaptation; Physiology; Play; Population; Primates; Property; Proxy; RNA Virus Infections; RNA Viruses; Recording of previous events; Resistance; Retinal blind spot; Risk; Rodent; Role; SARS coronavirus; Sampling; Severe Acute Respiratory Syndrome; Signal Transduction; Study models; Temperature; Testing; Uganda; Viral Antigens; Viral reservoir; Virulent; Virus; Virus Diseases; Virus-like particle; Work; Zoonoses; antigen challenge; antiviral immunity; experimental study; immune resistance; innate immune pathways; innovation; insight; malaria infection; male; novel; pathogen; pathogenic bacteria; pathogenic virus; predicting response; pregnant; prevent; response; transmission process

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.

抽象的 该项目的重点是了解蝙蝠的独特生理学在其充当能力中发挥的作用 宿主的储藏室可能会溢出到人类。该项目将在现场条件下进行 在乌干达，三种蝙蝠与埃博拉病毒（EBOV）与人类的传播有不同联系的蝙蝠。经过 比较这三种蝙蝠应对埃博拉类似免疫挑战的能力，这项工作将 帮助确定导致溢出风险的特征。从长远来看，这项工作将有助于确定主机 EBOV和其他相关病毒的物种，这些病毒对人类有风险。这也将有助于解释如何不同 蝙蝠的种类对不同类型的病毒感染反应。该项目的主要重点是确定 行为和分子途径，使储层宿主能够耐受感染，提供关键的见解 变成导致溢出的一种机制。这项工作是由某些蝙蝠物种的假设驱动的 已与特定类型的病毒感染共同发展，因此具有适应性的机制以最小化 感染过程中的病理。蝙蝠是全球生物多样性的，并且具有许多独特的生态和生理学 适应，包括飞行和使用过度并热体温的能力 规定。该项目的重点是选择三种蝙蝠物种，因为它们与人类密切接触， 他们的栖息地涵盖了EBOV暴露风险的范围，并且与 病毒病原体；这三个物种中有两个与EBOV流行病学有着显着联系。该项目解决 这些问题在野外的自然条件下采用了使用EBOV病毒样的创新方法 颗粒作为生化病原体实验感染的代理。这个项目有三个特定的 目标可以实现其目标。首先，该项目检验了特定非洲蝙蝠的假设 物种将显示出EBOV疾病耐受性的特征，以应对EBOV病毒样挑战 颗粒，因此很可能是天然储层宿主。这些实验将为您提供重大洞察力 蝙蝠的疾病耐受性以及EBOV水库的潜在身份。其次，该项目测试 蝙蝠表现出依赖于先天免疫途径的疾病耐受水平的假设 在蝙蝠中经历了独特的进化选择。第三，该项目探讨了容忍度是否 蝙蝠的独特代谢行为促进了对病毒感染的抵抗，即它们可以 降低代谢并进入Torpor以节省能量并可以提高新陈代谢，从而温度 在飞行过程中。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重要的免疫学耐受性和耐药性 疾病水库。共同完成这些目标将有助于确定是否感染 宽容赋予非洲蝙蝠物种，能够充当有毒的人畜共患病毒和 将确定有助于耐受性表型的分子，生理和行为机制。