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.

长期目标是表征蝙蝠免疫系统的细胞和分子成分。 小组一直致力于研究马尔堡病毒（MARV）从埃及 rosette（ERB， One Health 病原体监测计划的最终目标是控制蝙蝠。 确定最可能的病原体溢出源，以及更有可能促进屏障的做法 此后，出现的命运取决于病原体在人体内传播的能力。 假设是人畜共患宿主和人类之间的免疫学差异是 经过详细的基因组比较后，我们报告了溢出频率的重要决定因素。 与人类相比，多个免疫相关基因家族在 ERB 中进行了转基因扩增： 天然杀伤凝集素样受体-C（KLRC 或 NKG2）和 KLR-D（或 CD94）基因家族、MHC 的扩展 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。 已知在人类中发挥病毒保护作用；具有不同组织表达的功能性 IgE 基因的重复 四种 IgG 的模式和理论功能；独特的假定功能和结构特征； 与灵长类动物相比，IgG 的 FcR (FcγR) 缺乏扩展，并且具有潜在的不同功能； 完全不存在功能性短五聚蛋白。所有这些观察结果表明 ERB 建立了一个 在此，我们建议对 ERB 进行功能表征。 独特的 NK 和 IFN 免疫突触 该提案的目的是通过实验确认。 预测的基因组功能的基本原理是，耐受性可能是异常恢复能力的基础。 蝙蝠能够抵抗对人类具有高毒性和/或致命性的病毒感染。 测试所追求的 2 个具体目标： 1) 确定 NKG2-CD94 关联形成功能性功能的潜力 受体和异二聚体下游的信号传导，以评估 ERB NK 激活机制。 ; 确定 I 型 IFN 下游 ERB 的功能和信号级联，以测试是否扩增 IFN -ω 和 -α 与生物学差异相关，我们将利用创新的组合来追求它们。 免疫学技术利用 NIAID 在免疫细胞图谱方面的投资，以及单 细胞基因组学以及之前用于生成 ERB 特异性试剂的投资这项研究意义重大， 因为如果 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。 这项工作的近期预期成果是了解蝙蝠先天的特殊性 免疫系统及其基线状态的评估结果将立即呈阳性。 对 MARV 溢出研究的影响 此外，其他蝙蝠免疫系统也类似。 这项工作将为评估蝙蝠的免疫学特征奠定基础。