Dissecting novel mechanisms of dengue virus NS1-induced vascular leak

剖析登革热病毒 NS1 诱导血管渗漏的新机制

基本信息

  • 批准号:
    9221261
  • 负责人:
  • 金额:
    $ 38.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-02-15 至 2021-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Determining novel mechanisms of dengue virus NS1-induced vascular leak. The four dengue virus serotypes (DENV1-4) are mosquito-borne flaviviruses that cause ~100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that induce vasoactive cytokines, which cause endothelial disruption and vascular leakage leading to shock. To date, no viral proteins have been directly implicated in triggering endothelial permeability. DENV non-structural protein 1 (NS1) is secreted by infected cells and circulates in patients' blood during acute infection, and high levels of sNS1 are associated with severe disease. We have recently shown that injection of mice with DENV NS1 protein in the absence of virus induces both vascular leak and an increase in key inflammatory cytokines, while simultaneous administration of NS1 with a sublethal dose of DENV2 results in a lethal vascular leak syndrome. We have also demonstrated that NS1 from DENV1-4, but not from the related flavivirus West Nile virus (WNV), triggers endothelial barrier dysfunction and increased permeability of human endothelial cell monolayers in vitro. Finally, we found that NS1 vaccination and anti-NS1 antibodies can protect against NS1-mediated pathogenesis and endothelial permeability. These findings add an important and previously-overlooked component to the causes of dengue vascular leak, identify a new potential target for anti-dengue therapeutics, and support inclusion of NS1 in dengue vaccines. Here we propose to use the in vitro and in vivo models of DENV pathogenesis we have established to define the contributions of secreted NS1 protein to dengue pathogenesis. Our in vitro model allows us to examine the mechanism(s) of how NS1 leads to loss of endothelial barrier integrity, a key component of DENV pathogenesis resulting in vascular leak. Our murine model of DENV infection recapitulates vascular leak symptoms seen in humans, and we have developed both systemic and localized models of vascular permeability. In Aim 1, we will identify endothelial cell-specific responses to DENV NS1 and define the mechanism of NS1-induced endothelial permeability both in vitro and in vivo. In Aim 2, we will define the cytokine-dependent effector mechanisms activated by DENV NS1 and determine their relative contribution to NS1-dependent increases in vascular permeability in vivo and ex vivo. In Aim 3, using a structure/function approach with DENV/WNV NS1 chimeras and site-specific mutants, together with a battery of genetically deficient mice and inhibitors of specific host signaling pathways, we will determine the molecular determinants of NS1 that are responsible for pathogenic functions in vitro and in vivo. Overall, these studies will advance a critical new area of investigation regarding the novel functions of DENV NS1 in inducing vascular leak and define the molecular determinants of NS1-induced pathogenesis, directly contributing to improving our understanding of severe dengue disease and opening new pathways for treatment.


项目成果

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Eva Harris其他文献

Eva Harris的其他文献

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{{ truncateString('Eva Harris', 18)}}的其他基金

The evolution of dengue virus-reactive circulating antibody repertoire
登革热病毒反应性循环抗体库的进化
  • 批准号:
    10647572
  • 财政年份:
    2023
  • 资助金额:
    $ 38.27万
  • 项目类别:
Host factors and viral determinants mediating flavivirus NS1 tissue-specific endothelial dysfunction and vascular leak
介导黄病毒 NS1 组织特异性内皮功能障碍和血管渗漏的宿主因素和病毒决定因素
  • 批准号:
    10610896
  • 财政年份:
    2022
  • 资助金额:
    $ 38.27万
  • 项目类别:
Host factors and viral determinants mediating flavivirus NS1 tissue-specific endothelial dysfunction and vascular leak
介导黄病毒 NS1 组织特异性内皮功能障碍和血管渗漏的宿主因素和病毒决定因素
  • 批准号:
    10417735
  • 财政年份:
    2022
  • 资助金额:
    $ 38.27万
  • 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
  • 批准号:
    10615774
  • 财政年份:
    2021
  • 资助金额:
    $ 38.27万
  • 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
  • 批准号:
    10450165
  • 财政年份:
    2021
  • 资助金额:
    $ 38.27万
  • 项目类别:
Living in the post-Zika world: Impact of interactions between dengue and Zika viruses on diagnostics, antibody dynamics, and correlates of disease risk
生活在后寨卡世界:登革热和寨卡病毒之间的相互作用对诊断、抗体动态和疾病风险相关性的影响
  • 批准号:
    10297285
  • 财政年份:
    2021
  • 资助金额:
    $ 38.27万
  • 项目类别:
Evaluation of in vitro and in vivo efficacy of glycan-based compounds against flavivirus endothelial permeability and vascular leak
聚糖基化合物对抗黄病毒内皮通透性和血管渗漏的体外和体内功效评估
  • 批准号:
    10115592
  • 财政年份:
    2020
  • 资助金额:
    $ 38.27万
  • 项目类别:
Project 1 - Immune profiling of natural dengue virus infections
项目 1 - 天然登革热病毒感染的免疫分析
  • 批准号:
    10428796
  • 财政年份:
    2020
  • 资助金额:
    $ 38.27万
  • 项目类别:
Evaluation of in vitro and in vivo efficacy of glycan-based compounds against flavivirus endothelial permeability and vascular leak
聚糖基化合物对抗黄病毒内皮通透性和血管渗漏的体外和体内功效评估
  • 批准号:
    9979169
  • 财政年份:
    2020
  • 资助金额:
    $ 38.27万
  • 项目类别:
Administrative Supplement to R21: Mechanism and in vivo activity of novel glycan-based therapy against flavivirus endothelial permeability and vascular leak
R21 的行政补充:针对黄病毒内皮通透性和血管渗漏的新型聚糖疗法的机制和体内活性
  • 批准号:
    10265787
  • 财政年份:
    2020
  • 资助金额:
    $ 38.27万
  • 项目类别:

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