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.

项目概要 汉坦病毒是在世界各地的食虫动物和啮齿动物宿主中发现的人畜共患 RNA 病毒家族。旧的 世界汉坦病毒、汉坦病毒 (HTNV) 和首尔病毒 (SEOV) 是出血性肝炎的病原体 肾综合征发热（HFRS），亚洲最常见的出血热疾病。主要是汉坦病毒 通过不明确的方式以内皮细胞为目标进行感染并驱动血管渗漏和失调。 汉坦病毒在各自的储存宿主中建立无症状的持续感染。机制 这些不同感染结果的背后仍然未知，并且没有治疗 HFRS 的疗法。我们的 先前发表的数据表明，I 型干扰素 (IFN) 有效限制 HTNV 复制，并且 细胞质 RNA 识别受体 RIG-I 和 MDA5 是启动 I 型 IFN 反应所必需的 汉坦病毒感染期间的人内皮细胞。相比之下，在这里我们表明，SEOV 感染以其自然的方式 储库宿主在体外不会导致先天免疫转录激活，更有趣的是，IFNβ 治疗不会限制 SEOV 在储存细胞中的复制。此外，人类和 感染 SEOV 的大鼠内皮细胞揭示了显着的、宿主特异性的差异基因表达模式 干扰素和白细胞外渗途径。预测网络分析确定了差异调节 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，人内皮细胞的活化和迁移。这些数据，随着 该领域的大量文献证明 I 型干扰素对血管功能有显着影响，引导我们 假设人类 SEOV 感染后 I 型 IFN 信号传导驱动内皮细胞激活， 血管失调和促炎性中性粒细胞募集是 HFRS 的标志。更远， 我们假设 SEOV 的储存宿主，即普通大鼠，通过病毒诱导的病毒逃避了严重的疾病 抑制 I 型干扰素激活并减少炎症。我们将通过以下方式检验这个假设：1）剖析 启动和拮抗储存库和非储存库先天免疫的病毒-宿主相互作用，2) 研究 I 型 IFN 信号传导对 SEOV 感染的内皮细胞血管功能障碍的贡献，以及 3) 定义 I 型 IFN 信号传导在中性粒细胞激活和跨 SEOV 感染的内皮细胞外渗中的作用 来自储存库和人类宿主。虽然类似的比较免疫学方法可以理解 其他人畜共患 RNA 病毒的发病机制已取得成功，但大多数储存库的可处理性有限 啮齿动物宿主在汉坦病毒领域的进展受到严重限制。因此，有意选择学习 SEOV 及其天然储存库（常见的实验室大鼠）为我们提供了基因组和免疫学信息 资源来完成对免疫致病机制的新颖、深入的研究 人类汉坦病毒病。