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: 10513504
• 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/10513504
• 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; Consequentialism; 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; Lead; 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 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 汉坦病毒是在全球昆虫动物和啮齿动物宿主中发现的人畜共患病毒家族。旧 世界汉坦病毒，汉坦病毒（HTNV）和首尔病毒（SEOV）是出血的病因学药物 肾脏综合征发烧（HFRS），这是亚洲最常见的出血热疾病。汉坦病毒主要 靶向内皮细胞通过较差的平均值，用于感染并驱动血管泄漏和失调。 在各自的储层宿主中，汉坦病毒建立了渐近的持续感染。机制 这些不同的感染结果的基础仍然未知，并且没有治疗HFR的治疗性。我们的 先前发布的数据表明，I型干扰素（IFN）有效地限制了HTNV复制，并且 启动I型IFN响应需要的细胞质RNA识别受体RIG-I和MDA5是必需的 汉坦病毒感染期间人体内皮细胞。在这里，我们表明，相比之下，SEOV自然感染了 储层宿主不会在体外导致先天免疫转录激活，更有趣的是，IFNβ 处理不会限制储层细胞中的SEOV复制。此外，对人类和人类的全球转录组分析 被SEOV感染的大鼠内皮细胞揭示了罢工，降低基因表达的宿主特异性模式 IFN和白细胞渗出途径。预测的网络分析确定了对 血管内皮生长因子（VEGF）受体信号通路，基因表达相关的增加 与储层内皮细胞​​相比，人内皮细胞的激活和迁移。这些数据，沿着 该领域的大量文献证明了I型IFN对血管功能的显着影响，引导我们 为了假设人类SEOV感染后的I型IFN信号传导驱动内皮细胞激活， 血管失调，并募集促炎性中性粒细胞，这是HFRS的标志。更远， 我们假设普通大鼠的SEOV的储层宿主通过病毒诱导的 抑制I型IFN激活并减少注射。我们将通过：1）剖析此假设 启动和拮抗储层和非储液先天免疫的病毒宿主相互作用，2）研究 I型IFN信号对SEOV感染的内皮细胞中血管功能障碍的贡献，3）定义 I型IFN信号传导在SEOV感染的内皮细胞之间的中性粒细胞激活和渗出中的作用 来自水库和人类托管。而类似的比较免疫学方法来理解 其他人畜共患病毒病毒的发病机理已成功，大多数参考者的障碍性有限 啮齿动物宿主在汉塔病毒场的进展显着有限。那是有意学习的选择 SEOV及其天然储层是普通实验室大鼠，为我们提供了基因组和免疫学 资源完成小说，深入研究对免疫发育机制 人类汉坦病毒病。