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.

长期目标是确定蝙蝠免疫系统的细胞和分子组成。我们的 该小组一直在研究马尔堡病毒(Marv)的溢出和埃及鲁塞特(ERB)的传播， Aegyptiacus)蝙蝠。One Health病原体监测计划的最终目标是 确定最有可能的病原体溢出来源，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类体内传播的能力。我们的中央 假设人畜共患病宿主和人类之间的免疫学差异是 溢出效应频率的重要决定因素。在详细的基因组比较之后，我们报道了 与人类相比，ERB中经历了扩张的多个免疫相关基因家族： 自然杀伤分子凝集素样受体-C(KLRC或NKG2)和KLR-D(或CD94)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基因的拷贝数增加了 已知在人类中起病毒保护作用；具有不同组织表达的功能性IgE基因的复制 模式和理论功能：四个IGG的独特假定功能和结构特征； 与灵长类相比，缺乏免疫球蛋白FcR(FcγR)的扩展，以及潜在的不同功能；以及 完全没有功能性的短五肽。所有这些观察都表明，再培训局建立了一套 应对病原体感染的耐受性状态。在这里，我们建议从功能上描述雇员再培训局 独特的NK和干扰素免疫突触。这项建议的目的是从实验上证实 预测了基因组的功能。其基本原理是，宽容可能是人类具有超常韧性的基础 蝙蝠能够抵抗对人类具有高度致命性和/或致命性的病毒感染。中心假设将是 通过追求两个特定目标进行测试：1)确定NKG2-CD94结合潜力形成功能性 受体和信号转导下游的异二聚体，以评估ERB NK的激活机制；2) 确定功能和信令级联下行ERB I型IFN以测试是否扩展 干扰素-ω和-α与生物学差异有关。我们将使用创新的组合来追求它们 利用NIAID在免疫细胞图谱上的投资的免疫技术，以及单一的- 细胞基因组学以及以前生产ERB特异性试剂的投资。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中间阶段推进知识，如果 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。这个 这项工作的直接预期结果是对蝙蝠天生的特殊性的理解 免疫系统及其基线状态的评估。结果将立即产生积极的影响 对Marv溢出效应研究的影响。此外，由于其他蝙蝠免疫系统类似 这项工作将为评估蝙蝠的免疫学特征奠定基础。