SHINING A LIGHT ON BAT CELLULAR IMMUNITY FOLLOWING VIRUS INFECTION

揭示病毒感染后蝙蝠细胞免疫

基本信息

批准号：
10449406
负责人：
MICHELLE L BAKER
金额：
$ 15.02万
依托单位：
COMMONWEALTH SCIENTIFIC & INDUST RES ORG
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449406
关键词：
2019-nCoV Accounting Adaptive Immune System Animals Antibodies Antigens Antiviral Response Australia Biological Assay Biology CD8B1 gene Cells Cellular Immunity Characteristics Chiroptera Clinical Containment Dangerousness Development Diagnosis Disease Epitopes Equus caballus Evolution Family Pteropodidae Family suidae Far East Fatality rate Ferrets Fossils Generations Genus Pteropus Goals Habitats Hendra Virus Henipavirus Human Immune Immune response Immune system Immunity Immunohistochemistry Immunology Immunology procedure In Situ Infection Innate Immune Response Interferon-alpha Intervention Lead Light Mammals Mediating Modeling Monitor Monoclonal Antibodies Nipah Virus Outcome Pathogenesis Pathogenicity Peptide/MHC Complex Peptides Protein Chemistry Proteomics RNA Viruses Readiness Reagent Respiratory Disease Stains T-Cell Receptor T-Lymphocyte Universities Validation Viral Virus Virus Diseases Virus Replication Virus Shedding Work Zoonoses adaptive immune response bat-borne cell mediated immune response cytokine flu infancy innovation insight mortality nervous system disorder novel novel therapeutics novel vaccines pathogen prevent protein expression receptor tool transcriptome transcriptome sequencing

项目摘要

Project summary/abstract Bats are important reservoir hosts for a variety of viruses, several of which are associated with fatality rates as high as 90% among diagnosed human cases. This includes the highly pathogenic henipaviruses, of which Hendra virus (HeV) emerged in Australia and Nipah virus (NiV) in South-east Asia via horse and pig intermediate hosts respectively. The henipaviruses have been shown to be transmitted from Pteropus bats, with the Australian black flying fox (Pteropus alecto) confirmed as a reservoir for HeV (1, 2). As with other viral infections in bats, natural or experimental infection of bats with HeV causes no clinical signs of disease despite shedding of virus. The antiviral immune response of P. alecto is among the most well studied of all bat species, with novel immune mechanisms already discovered including the constitutive expression of interferon alpha discovered by our team (3). These characteristics make the P. alecto – HeV model uniquely suited to answering the questions we propose in this project. Despite the increasing emergence of zoonotic viruses from bats, studies of bat immunology remain in their infancy and few studies have examined the adaptive immune responses of any bat species. Understanding the antiviral responses in bats is crucial if we are to predict and prevent virus spillover from bats to other susceptible species, understand disease pathogenesis in other mammals and uncover new therapeutics and vaccines to treat these diseases in humans and other animals. In this study, we will characterise the innate and adaptive immune response of experimentally infected bats to HeV to obtain detailed insights into how bats control viral infection. The cell mediated immune response of bats will be dissected using functional assays to determine the subsets of cells activated during an active infection and explore global gene and protein expression to characterise the innate and adaptive immune response of infected bats. The use of innovative approaches to identify MHC bound HeV peptides in infected bats, building on previous bat immunopeptidomics studies, will provide new insights into peptide presentation during infection. Few studies have comprehensively studied the immune response of bats during infection, and none have examined the functional activation of the cell mediated immune response. Comparison with infected ferrets will allow us to directly compare mechanisms responsible for innocuous (bats) compared to fatal (ferrets) HeV infection. Expected outcomes include understanding the basic biology of antiviral responses in bats and the development of new tools to monitor bat immunity to HeV and related viruses. The Australian Centre for Disease Preparedness and Monash University are uniquely suited for performing the work outlined in this proposal with a strong track record of working together on bat immunology. The team has access to high containment facilities and expertise to perform animal infections with dangerous pathogens combined with access to protein chemistry facilities and expertise in generating tetramer reagents.

项目概要/摘要蝙蝠是多种病毒的重要储存宿主，其中一些病毒与死亡率相关，例如人类确诊病例中高达 90%，其中包括高致病性亨尼帕病毒。亨德拉病毒（HeV）在澳大利亚出现，尼帕病毒（NiV）在东南亚通过马和猪出现亨尼帕病毒分别被证明是从翼蝠属蝙蝠传播的。与其他病毒一样，澳大利亚黑狐蝠 (Pteropus alecto) 被证实是 HeV 的宿主 (1, 2)。蝙蝠感染 HeV，自然或实验性感染 HeV 不会导致疾病的临床症状，尽管 P. alecto 的抗病毒免疫反应是所有蝙蝠物种中研究最深入的。已发现新的免疫机制，包括干扰素α的组成型表达我们团队发现的这些特征使得 P. alecto – HeV 模型特别适合回答我们在这个项目中提出的问题。蝙蝠，蝙蝠免疫学的研究仍处于起步阶段，很少有研究检查适应性免疫如果我们要预测和预测任何蝙蝠物种的反应，那么了解蝙蝠的抗病毒反应至关重要。防止病毒从蝙蝠传播到其他易感物种，了解其他疾病的发病机制哺乳动物并发现新的疗法和疫苗来治疗人类和其他动物的这些疾病。在这项研究中，我们将描述实验感染蝙蝠的先天性和适应性免疫反应 HeV 获得有关蝙蝠如何控制病毒感染的详细见解细胞介导的蝙蝠免疫反应。将使用功能分析进行剖析，以确定活跃感染期间激活的细胞亚群并探索全局基因和蛋白质表达，以表征先天性和适应性免疫反应使用创新方法识别受感染蝙蝠中 MHC 结合的 HeV 肽，构建在之前的蝙蝠免疫肽组学研究中，将为肽呈现提供新的见解很少有研究全面研究蝙蝠在感染期间的免疫反应，也没有一项研究。检查了细胞介导的免疫反应的功能激活与感染的比较。雪貂将使我们能够直接比较无害（蝙蝠）与致命的机制（雪貂）HeV 感染的预期结果包括了解抗病毒反应的基本生物学。蝙蝠以及监测蝙蝠对 HeV 和相关病毒免疫力的新工具的开发。澳大利亚疾病预防中心和莫纳什大学非常适合开展该提案中概述的工作在蝙蝠免疫学方面有着良好的合作记录。使用高密闭设施和专业知识来进行危险病原体的动物感染结合蛋白质化学设施和生成四聚体试剂的专业知识。