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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：
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
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/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

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.

项目总结