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

基本信息

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
项目类别：
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

项目摘要

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。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，主要由汉坦病毒引起。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。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 反应所必需的相比之下，汉坦病毒感染期间的人类内皮细胞。宿主储存库不会导致体外先天免疫转录激活，更有趣的是，IFNβ 治疗并不限制 SEOV 在储存细胞中的复制。此外，对人类和人类的整体转录组分析。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预测的网络分析确定了干扰素和白细胞外渗途径的差异调节。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，人内皮细胞的激活和迁移以及这些数据。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，引导我们重新捕获人类 SEOV 感染后 I 型 IFN 信号驱动内皮细胞激活，血管失调和促炎性中性粒细胞募集是 HFRS 的标志。我们相信 SEOV 的储存宿主，即普通老鼠，通过病毒诱导的病毒逃避了严重的疾病。抑制 I 型 IFN 激活并减少炎症我们将通过以下方式检验这一假设：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) 调查 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活化和跨 SEOV 感染的内皮细胞外渗中的作用来自宿主和人类宿主的相似的比较免疫学方法来理解。其他人畜共患病 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明显受到限制，因此，有意选择研究。 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完成对免疫致病潜在机制的新颖、深入研究的资源人类汉坦病毒病。