Functional Characterization of Egyptian rousette Bat Innate immune synapses

埃及莲座蝙蝠先天免疫突触的功能表征

• 批准号: 10451027
• 负责人: Gustavo F. Palacios
• 金额: $ 25.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451027
• 关键词: Affinity; Atlases; Biological; Biology; C-reactive protein; CD94 Antigen; Case Fatality Rates; Cells; Characteristics; Chiroptera; Event; Fostering; Frequencies; Gene Family; Genes; Genome; Genomics; Goals; Health; Human; IgE; Immune; Immune system; Immunity; Immunoglobulin G; Immunologic Techniques; Immunologics; Individual; Infection; Inflammation; Innate Immune System; Interferon Type I; Interferon Type II; Interferons; Interphase; Investments; KLRD1 gene; Knowledge; Lectin; MHC Class I Genes; Mammals; Marburgvirus; Mission; Modeling; Molecular; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Pattern; Population; Primates; Public Health; Reagent; Receptor Signaling; Reporting; Research; Rousettus; Seminal; Serum Amyloid P-Component; Severity of illness; Signal Transduction; Source; Surveillance Program; Testing; Tissues; United States National Institutes of Health; V(D)J Recombination; Viral; Virulent; Virus Diseases; Work; Zoonoses; genomic predictors; immunological status; immunological synapse; innovation; pandemic disease; pathogen; pathogen spillover; pathogenic virus; receptor; research and development; resilience; transmission process; zoonotic spillover

The long-term goal is to characterize the cellular and molecular constituents of the bat immune system. Our group had been working on Marburg virus (MARV) spillover and transmission from Egyptian rousette (ERB, Rousettus aegyptiacus) bats. The ultimate goal of One Health pathogen surveillance programs is the identification of the most likely source of pathogen spillovers, and the practices more likely to facilitate the barrier jump. After this, the fate of emergence depends on the pathogen ability to transmit within humans. Our central hypothesis is that the immunological differences between the zoonotic host and humans are a significant determinant of the frequency of spillovers. After a detailed genome comparison, we reported multiple immune-related gene families that have undergone expansion in ERB compared to humans: the expansion of natural Killer Lectin-like Receptor-C (KLRC or NKG2) and KLR-D (or CD94) gene families, MHC Class I genes and type I interferon -ω and -α. Later, we revealed an increase in copy number of IGHV genes known to act in viral protection in humans; a duplication of functional IgE genes with different tissue expression patterns and theoretical functions; distinctive putative functions and structural characteristics of the four IgGs; lack of expansion of FcR for IgG (FcγR) compared to primates and potential different functionality; and the complete absence of functional short pentraxins. All these observations indicate that ERB establishes a tolerogenic state to deal with pathogen infection. Here, we propose to functionally characterize ERBs unique NK and IFN immunological synapses. The objective of this proposal is to confirm experimentally the predicted genomic functionality. The rationale is that Tolerance could be the basis for the unusual resilience of bats to withstand viral infections that are highly virulent and/or lethal in humans. The central hypothesis will be tested by pursuing 2 specific aims: 1) To determine the NKG2-CD94 association potential to form a functional receptor and the signaling downstream of the heterodimers to evaluate ERB NK activation mechanisms.; 2) To determine functionality and signaling cascade downstream ERBs Type I IFNs to test whether the expansion of IFN -ω and -α correlates with biological differences. We will pursue them using an innovative combination of immunological techniques that take advantage from NIAID investments in the Atlas of Immune Cells, and single- cell genomics as well as previous investments to generate ERB specific reagents. This research is significant, because it will advance knowledge at the crucial interphase that determine transmission and pathogenesis if the differences between the immunological status of different mammals are a driver for zoonotic spillovers. The proximate expected outcome of this work is an understanding of the particularities of the bat innate immunological system and an assessment of its baseline status. The results will have an immediate positive impact on the studies on MARV spillover. Moreover, as other bat immunological systems are similarly characterized, this work will lay the groundwork to assess bats immunological features.

长期目标是表征蝙蝠免疫系统的细胞和分子构成。我们的 Group一直在研究Marburg病毒（Marv）Spilover和埃及Rousette（Erb，Erb， Rousettus aegyptiacus）蝙蝠。一个健康病原体监测计划的最终目标是 鉴定最有可能的病原体杂质的来源，而实践更有可能促进屏障 跳。此后，出现的命运取决于病原体在人类内传播的能力。我们的中心 假设是人畜共患宿主与人之间的免疫学差异是 明显确定了Spilovers的频率。经过详细的基因组比较，我们报告了 与人相比，在ERB中经历了多个与免疫相关的基因家族： 天然杀手型凝集素样受体C（KLRC或NKG2）和KLR-D（或CD94）基因家族的扩展，MHC I类基因和类型I干扰素-Ω和-α。后来，我们揭示了IGHV基因的拷贝数增加 众所周知，在人类的病毒保护中行动；具有不同组织表达的功能性IgE基因的重复 模式和理论功能；四个IgG的独特推定功能和结构特征； 与主要和潜在的功能相比，IgG（FCγR）缺乏FCR的扩展；和 完全缺乏功能短五肽。所有这些观察结果表明ERB建立了 耐受性处理病原体感染的状态。在这里，我们建议在功能上表征ERB 独特的NK和IFN免疫突触。该提议的目的是通过实验确认 预测的基因组功能。理由是，公差可能是具有异常韧性的基础 蝙蝠承受人类高毒和/或致命的病毒感染。中心假设将是 通过追求2个特定目的测试：1）确定NKG2-CD94的关联潜力以形成功能 受体和异二聚体下游的信号传导评估ERB NK活化机制。 2）到 确定功能和信号传导级联向下游ERB I型IFN型，以测试是否扩展 IFN-Ω和-α与生物学差异相关。我们将使用创新的组合来追求它们 从免疫细胞地图集中利用NIAID投资的免疫学技术，单一 细胞基因组学以及以前的投资生成特定于ERB的试剂。这项研究很重要， 因为它将在确定传播和发病机理的关键相之间的了解 不同哺乳动物的免疫学状态之间的差异是人畜共患病的驱动因素。 这项工作的直接预期结果是对蝙蝠先天的特殊性的理解 免疫系统及其基线状况的评估。结果将立即积极 对MARV Spilover的研究影响。此外，由于其他BAT免疫系统也一样 特征是，这项工作将为评估蝙蝠免疫学特征的基础奠定基础。