SHINING A LIGHT ON BAT CELLULAR IMMUNITY FOLLOWING VIRUS INFECTION

揭示病毒感染后蝙蝠细胞免疫

• 批准号: 10618969
• 负责人: MICHELLE L BAKER
• 金额: $ 14.61万
• 依托单位: COMMONWEALTH SCIENTIFIC & INDUST RES ORG
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-06 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618969
• 关键词: 2019-nCoV; Accounting; Adaptive Immune System; Animals; Antibodies; Antigens; Antiviral Response; Australia; Binding; Biological Assay; Biology; CD8B1 gene; Cells; Cellular Immunity; Characteristics; Chiroptera; Clinical; Containment; Dangerousness; Development; Diagnosis; Disease; Epitopes; Equus caballus; Evolution; Family Pteropodidae; Family suidae; 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; Light; Mammals; Mediating; Modeling; Monitor; Monoclonal Antibodies; Nipah Virus; Outcome; Pathogenesis; Pathogenicity; Peptide/MHC Complex; Peptides; Predisposition; Protein Chemistry; Proteomics; RNA Viruses; Readiness; Reagent; Respiratory Disease; Simuliidae; Southeastern Asia; 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; constitutive expression; cytokine; flu; infancy; innovation; insight; mortality; nervous system disorder; novel; novel therapeutics; novel vaccines; pathogen; prevent; protein expression; receptor; tool; transcriptome; transcriptome sequencing; transmission process

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.

项目摘要/摘要 蝙蝠是各种病毒的重要储层宿主，其中一些与死亡率有关 在诊断性人类病例中高达90％。这包括高度致病性的Henipaviruse，其中 Hendra病毒（HEV）在澳大利亚出现，Nipah病毒（NIV）通过马和猪在东南亚出现 中间主机分别。 HENIPAVIRAS已显示已从pteropus蝙蝠传播， 澳大利亚黑色飞狐（pteropus alecto）被确认为HEV的水库（1，2）。与其他病毒一样 蝙蝠的感染，自然或实验感染HEV的感染不会引起疾病目的地的临床迹象 脱落病毒。 Alecto的抗病毒免疫反应是所有BAT物种中最精心研究的抗病毒反应， 已经发现了新型免疫机制，包括干扰素α的本构表达 由我们的团队发现（3）。这些特征使P. Alecto - HEV模型独特适合 回答我们在这个项目中提出的问题。尽管人畜共动性病毒的出现越来越多 蝙蝠，对蝙蝠免疫学的研究仍在其起步阶段，很少有研究检查适应性免疫学 任何蝙蝠物种的反应。如果我们要预测和 防止从蝙蝠进入其他易感物种的病毒spilover，了解其他疾病发病机理 哺乳动物，发现新的疗法和疫苗，以治疗人类和其他动物中的这些疾病。 在这项研究中，我们将表征实验感染的蝙蝠的先天和适应性免疫反应 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响应 将使用功能测定法解剖以确定活性感染中激活的细胞子集 并探索全球基因和蛋白质表达，以表征 感染的蝙蝠。使用创新方法来识别受感染蝙蝠的MHC绑定的HEV Pepperides，建造 在先前的BAT免疫肽学研究中，将为肽表现提供新的见解 感染。很少有研究全面研究了感染过程中蝙蝠的免疫反应，没有 已经检查了细胞介导的免疫响应的功能激活。与感染的比较 雪貂将使我们能够直接比较负责无害（蝙蝠）的机制 （雪貂）HEV感染。预期的结果包括了解抗病毒反应的基本生物学 蝙蝠和开发新工具来监测对HEV和相关病毒的蝙蝠免疫力。 澳大利亚疾病准备中心和莫纳什大学非常适合执行 在该提案中概述的工作概述了与BAT免疫学共同努力的良好记录。团队有 使用危险病原体进行动物感染的高遏制设施和专业知识 结合获得蛋白质化学设施和产生四聚体试剂的专业知识。