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.

项目总结 汉坦病毒是一类人畜共患的RNA病毒，存在于世界各地的昆虫和啮齿动物宿主中。《老者》 世界汉坦病毒，汉滩病毒(HTNV)和首尔病毒(SEOV)是出血性疾病的病原体 肾综合征出血热(HFRS)，亚洲最常见的出血热疾病。以汉坦病毒为主 以内皮细胞为感染靶点，通过模糊的方式驱动血管渗漏和调节失调。 在它们各自的宿主中，汉坦病毒建立无症状的、持续的感染。其作用机制 在这些不同感染结果的基础上，目前尚不清楚，也没有治疗肾综合征出血热的治疗方法。我们的 以前发表的数据表明，I型干扰素(干扰素)有效地限制了HTNV的复制，并且 胞质RNA识别受体RIG-I和MDA5是启动I型干扰素应答所必需的 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感染在其自然状态下 水库宿主在体外不会导致天然免疫转录激活，更有趣的是，干扰素β也不会导致天然免疫转录激活 治疗并不限制SEOV在储藏细胞中的复制。此外，对人类和人类的全球转录分析 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不同的调控 血管内皮生长因子受体信号通路，与基因表达增加相关 与储藏内皮细胞相比，人内皮细胞的活化和迁移。这些数据，以及 根据该领域的大量文献显示I型干扰素对血管功能有显著影响，请引导我们 假设人类感染SEOV后的I型干扰素信号驱动内皮细胞激活， 血管调节失调和促炎性中性粒细胞募集是HFRS的特征。此外， 我们假设，SEOV的宿主，普通的大鼠，通过病毒诱导逃避严重的疾病 抑制I型干扰素的激活，减轻炎症。我们将通过以下方式验证这一假设：1)解剖 病毒-宿主相互作用启动和拮抗宿主和非宿主的天然免疫，2)调查 I型干扰素信号在SEOV感染的内皮细胞血管功能障碍中的作用，以及3)确定 I型干扰素信号在SEOV感染内皮细胞中性粒细胞激活和外溢中的作用 从水库和人类宿主那里。虽然类似的比较免疫学方法可以理解 对于其他人畜共患核糖核酸病毒的致病机制已经成功，多数宿主的处理能力有限 啮齿动物宿主在汉坦病毒领域的进展非常有限。因此，有意选择进行研究 SEOV及其天然储存库，普通的实验室大鼠，为我们提供了基因组和免疫学 资源以完成一项新的、深入的免疫致病机制调查 人类中的汉坦病毒病。