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: 10576965
• 负责人: Gustavo F. Palacios
• 金额: $ 21.13万
• 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/10576965
• 关键词: Affinity; Atlases; Biological; Biology; C-reactive protein; CD94 Antigen; Case Fatality Rates; Cells; Characteristics; Chiroptera; Creativeness; Event; Fostering; Frequencies; Gene Family; Genes; Genome; Genomics; Goals; Health; Health protection; 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; 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; functional genomics; genomic predictors; immunological status; immunological synapse; innovation; pandemic potential; 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.

长期目标是描述蝙蝠免疫系统的细胞和分子成分。我们 该小组一直在研究马尔堡病毒（MARV）从埃及鲁塞特（ERB， 埃及红蝠（Rousettus aegyptiacus）蝙蝠。One Health病原体监测计划的最终目标是 确定病原体溢出的最可能来源，以及更有可能促进屏障的做法 跳.在此之后，出现的命运取决于病原体在人体内传播的能力。我们的中央 一种假说认为，人畜共患病宿主和人类之间的免疫学差异是一种 溢出效应发生频率的重要决定因素。经过详细的基因组比较，我们报告说， 与人类相比，在ERB中经历了扩展的多个免疫相关基因家族： 天然杀伤凝集素样受体-C（KLRC或NKG 2）和KLR-D（或CD 94）基因家族，MHC的扩增 I类基因和I型干扰素-ω和-α。后来，我们发现IGHV基因的拷贝数增加， 已知在人体中起病毒保护作用;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;四种IgG独特的推定功能和结构特征; 与灵长类动物相比，IgG的FcR（FcγR）缺乏扩增，功能可能不同; 完全没有功能性短五聚素。所有这些观察结果显示，再培训局建立了一个 耐受原性状态以应对病原体感染。在这里，我们建议在功能上表征ERBs 独特的NK和IFN免疫突触。本提案的目的是通过实验证实 预测的基因组功能。理由是，宽容可能是不寻常的弹性的基础， 蝙蝠抵御病毒感染是高度致命的和/或致命的人类。核心假设是 通过追求2个具体目标进行测试：1）确定NKG 2-CD 94结合潜力，以形成功能性的 受体和异源二聚体下游的信号传导，以评估ERB NK激活机制。2)到 确定下游ERB I型IFN的功能和信号级联，以测试是否扩展 IFN -ω和IFN-α与生物学差异相关。我们将采用以下创新组合来实现这些目标 免疫学技术，利用NIAID在免疫细胞图谱中的投资， 细胞基因组学以及以前的投资，以产生ERB特异性试剂。这项研究意义重大， 因为它将在决定传播和发病机制的关键间期推进知识， 不同哺乳动物的免疫状态之间的差异是人畜共患病溢出的驱动因素。的 这项工作的最接近的预期结果是了解蝙蝠先天的特殊性， 免疫系统和评估其基线状态。结果会立即产生积极影响 对MARV溢出效应研究的影响。此外，与其他蝙蝠免疫系统类似， 特征，这项工作将奠定基础，评估蝙蝠的免疫功能。