Role of Type I IFN Signaling in Seoul Orthohantavirus Pathogenesis

I 型干扰素信号传导在首尔正汉坦病毒发病机制中的作用

• 批准号: 10668522
• 负责人: Alison Kell
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668522
• 关键词: Adherens Junction; Antiviral Response; Asia; Automobile Driving; Binding; Biomedical Research; Blood; Blood Vessels; Cardiopulmonary; Case Fatality Rates; Cell physiology; Cells; Coagulation Process; Connexins; Cytoplasm; Data; Disease; Disease Outcome; Endothelial Cells; Endothelial Growth Factors Receptor; Endothelium; Etiology; Extravasation; Family; Gene Expression; Genetic; Genomics; Hantaan virus; Hantavirus; Hantavirus Infections; Hemorrhagic Fever with Renal Syndrome; Human; Immune; Immune signaling; Immunologics; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inhalation; Interferon Activation; Interferon Type I; Interferons; Investigation; Kidney; Laboratory Rat; Leukocytes; Literature; Location; Lung; Mediating; Modeling; Molecular; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Outcome; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Pattern; Permeability; Platelet Activation; Publishing; RNA; RNA Viruses; Rattus; Rattus norvegicus; Regulation; Regulatory T-Lymphocyte; Resources; Rodent; Role; Seoul virus; Signal Induction; Signal Pathway; Signal Transduction; Site; Source; Stimulus; Syndrome; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Transcriptional Activation; Vascular Diseases; Vascular Endothelial Growth Factors; Viral; Viral Hemorrhagic Fevers; Virus Diseases; Virus Replication; Work; Zoonoses; antagonist; cell motility; chemokine; chronic infection; comparative; cytokine; human disease; immune activation; in vivo; infected vector rodent; innate immune mechanisms; migration; neutrophil; novel; pathogen; preservation; receptor; recruit; response; tool; transcriptomics; vascular inflammation; viral detection; virus host interaction; wound healing

PROJECT SUMMARY Hantaviruses are a family of zoonotic RNA viruses found in insectivore and rodent hosts worldwide. The Old World hantaviruses, Hantaan virus (HTNV) and Seoul virus (SEOV), are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS), the most common hemorrhagic fever disease in Asia. Hantaviruses primarily target endothelial cells for infection and drive vascular leakage and dysregulation, through poorly defined means. In their respective reservoir hosts, hantaviruses establish asymptomatic, persistent infections. The mechanisms underlying these divergent infection outcomes remain unknown and no therapeutic exists to treat HFRS. Our previously published data demonstrates that type I interferon (IFN) effectively limits HTNV replication and that the cytoplasmic RNA recognition receptors RIG-I and MDA5 are required for initiating the type I IFN response in human endothelial cells during hantavirus infection. Here we show that, in contrast, SEOV infection in its natural reservoir host does not result in innate immune transcriptional activation in vitro and, more interestingly, IFNβ treatment does not limit SEOV replication in reservoir cells. Further, global transcriptomic analysis of human and rat endothelial cells infected with SEOV reveal striking, host-specific patterns of differential gene expression for the IFN and leukocyte extravasation pathways. Predicted network analysis identified differential regulation of the vascular endothelial growth factor (VEGF) receptor signaling pathway, with increased gene expression related to activation and migration in human endothelial cells compared to reservoir endothelial cells. These data, along with substantial literature in the field demonstrating a significant effect of type I IFN on vascular function, lead us to hypothesize that type I IFN signaling following SEOV infection in humans drives endothelial cell activation, vascular dysregulation, and recruitment of proinflammatory neutrophils that are the hallmarks of HFRS. Further, we hypothesize that the reservoir host for SEOV, the common rat, escapes severe disease through viral-induced inhibition of type I IFN activation and reduced inflammation. We will test this hypothesis by: 1) dissecting the virus-host interactions that initiate and antagonize reservoir and non-reservoir innate immunity, 2) investigating the contribution of type I IFN signaling to vascular dysfunction in SEOV-infected endothelial cells, and 3) defining the role of type I IFN signaling in neutrophil activation and extravasation across SEOV-infected endothelial cells from reservoir and human hosts. While similar comparative immunology approaches to understanding pathogenesis for other zoonotic RNA viruses have been successful, the limited tractability of most reservoir rodent hosts has significantly limited progress in the hantavirus field. Thus, the intentional selection to study SEOV and its natural reservoir, the common laboratory rat, provides us with the genomic and immunologic resources to complete a novel, in depth investigation into the immunopathogenic mechanisms underlying hantavirus disease in humans.

项目摘要 汉坦病毒是一种人畜共患RNA病毒家族，在世界范围内的食虫动物和啮齿动物宿主中发现。老 汉坦病毒（Hantaan virus，HTNV）和首尔病毒（Seoul virus，SEOV）是世界上流行的两种汉坦病毒， 肾综合征出血热（HFRS）是亚洲最常见的出血热疾病。汉坦病毒主要 靶向内皮细胞进行感染，并通过定义不明确的方式驱动血管渗漏和失调。 汉坦病毒在其各自的储存宿主中建立无症状的持续感染。的机制 这些不同的感染结果的根本原因仍然未知，并且没有治疗HFRS的治疗方法。我们 先前发表的数据表明I型干扰素（IFN）有效地限制HTNV复制， 胞质RNA识别受体RIG-1和MDA 5是启动I型IFN应答所必需的， 汉坦病毒感染过程中的人内皮细胞。在这里，我们表明，相比之下，SEOV感染在其自然 储存宿主在体外不会导致先天免疫转录激活，更有趣的是，IFNβ 处理不限制SEOV在储库细胞中的复制。此外，人类和哺乳动物的全局转录组学分析 感染SEOV的大鼠内皮细胞显示出显著的宿主特异性差异基因表达模式， 干扰素和白细胞外渗途径。预测网络分析确定了差异调节的 血管内皮生长因子（VEGF）受体信号通路，与基因表达增加相关 与储库内皮细胞相比，人内皮细胞中的活化和迁移。这些数据，沿着 大量文献表明I型IFN对血管功能有显著影响， 为了假设人中SEOV感染后I型IFN信号传导驱动内皮细胞活化， 血管失调和促炎性中性粒细胞的募集是HFRS的标志。此外，本发明还 我们假设SEOV的储库宿主，普通大鼠，通过病毒诱导的免疫反应逃避严重的疾病。 抑制I型IFN活化和减少炎症。我们将通过以下方式来检验这一假设：1）解剖 启动和拮抗储库和非储库先天免疫的病毒-宿主相互作用，2）研究 I型IFN信号传导对SEOV感染的内皮细胞中血管功能障碍的贡献，以及3）定义 I型干扰素信号在SEOV感染内皮细胞中性粒细胞活化和外渗中作用 从宿主和人类宿主身上虽然类似的比较免疫学方法可以理解 其他人畜共患RNA病毒的致病机制已经成功，但大多数宿主的可处理性有限， 啮齿类宿主显著限制了汉坦病毒领域的进展。因此，有意选择研究 SEOV和它的天然宿主，普通实验室大鼠，为我们提供了基因组和免疫学研究。 资源，以完成一个新的，深入调查免疫病理机制的基础 人类的汉坦病毒病