Roles of secreted NS1 and NS1 antibody in dengue virus infection and immunity
分泌型NS1和NS1抗体在登革热病毒感染和免疫中的作用
基本信息
- 批准号:7675060
- 负责人:
- 金额:$ 29.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAntibodiesBindingBloodBlood CirculationBlood VesselsCellsCellular TropismCessation of lifeClinical TrialsComplementCytoplasmDengueDengue Hemorrhagic FeverDengue Shock SyndromeDengue VirusDevelopmentDiseaseDisease ProgressionEmerging Communicable DiseasesEvaluationHawaiiHumanImmuneImmunityIn VitroInfectionInfectious Diseases ResearchInterferon ReceptorKineticsMeasuresMusNicaraguaNonstructural ProteinOutputPathogenesisPeripheralPlayPredispositionProspective StudiesProteinsRoleSerotypingSerumSeverity of illnessSurfaceSyndromeTestingThrombocytopeniaTissuesVaccinationVaccinesViralViral Load resultVirus Diseasesbiodefensecellular targetinghepatoma cellin vitro Assayin vitro testingin vivoin vivo Modelmouse modeltherapeutic vaccinevirus pathogenesis
项目摘要
Dengue virus (DV) infection causes a spectrum of disease ranging from self-limited Dengue Fever to lifethreatening
Dengue Hemorrhagic Fever/Dengue Shock Syndrome. The mechanisms of immune protection
and pathogenesis are poorly understood, but DV nonstructural protein 1 (NS1) likely plays a key role. NS1 is
present in the cytoplasm and on the surface of infected cells and is secreted in a soluble form (sNS1) that
circulates in blood, where high sNS1 concentration correlates with increased disease severity. In vitro, sNS1
can activate complement, bind to infected and uninfected cells, and increase viral output from infected hepatoma
cells. However, it is unclear if or how sNS1 affects viral dissemination or disease progression in vivo.
Similarly, the role of antibodies (Abs) against NS1 is unclear due to the lack of appropriate in vivo models.
Anti-NS1 Abs display protective activity against neurovirulent death in mice, but the effects of anti-NS1 Abs
on DV infection of more relevant peripheral tissues have never been characterized. Nonetheless, NS1 is
included in several DV vaccines under development, including that of our collaborator, Hawaii Biotech, Inc.,
and no test exists to evaluate the repertoire of Abs generated by either natural infection or vaccination. We
have shown that DV infection of interferon receptor-deficient mice reproduces key features of human DV
infection, including susceptibility to all four DV serotypes with relevant infection kinetics, appropriate tissue
and cellular tropism, sNS1 circulation in the blood, thrombocytopenia correlated with viral load, and fatal
vascular leak syndrome. We will use this mouse model to examine the functions of sNS1 and the effects of
anti-NS1 Abs on DV infection. We will also use sera obtained from mice, prospective studies of dengue in
Nicaragua, and dengue vaccine trials to generate in vitro assays to assess the repertoire of anti-NS1 Abs in
infected mice, primary and secondary natural DV infections, and vaccine recipients. In Specific Aim 1, we
will assess the localization and function of sNS1 during DV infection in mice and fatal human dengue cases.
In Specific Aim 2, the effects of anti-NS1 Abs on peripheral DV infection in mice will be evaluated. We will
measure the ability of both polyclonal Abs and MAbs against NS1 to protect against DV infection using both
NS1 vaccination and MAbs against DV2 NS1, and we will screen for any detrimental in vivo effects of NS1
Abs. Finally, in Specific Aim 3, we will characterize the repertoire of anti-NS1 Abs generated by DV infection
and vaccination and will develop in vitro tests to detect anti-NS1 Abs in human serum likely to have
protective or pathogenic effects during subsequent DV infection. Together, these results will both elucidate
mechanisms of DV pathogenesis and contribute to the development of a safe and effective dengue vaccine.
登革病毒(DV)感染引起一系列疾病,从自限性登革热到危及生命的登革热,
登革出血热/登革休克综合征。免疫保护机制
和发病机制知之甚少,但DV非结构蛋白1(NS 1)可能起着关键作用。ns 1在所
存在于感染细胞的细胞质和表面上,并以可溶性形式(sNS 1)分泌,
在血液循环中,高sNS 1浓度与疾病严重程度增加相关。体外,sNS 1
可以激活补体,结合感染和未感染的细胞,并增加感染的肝癌的病毒输出
细胞然而,尚不清楚sNS 1是否或如何影响体内病毒传播或疾病进展。
类似地,由于缺乏适当的体内模型,针对NS 1的抗体(Abs)的作用尚不清楚。
抗NS 1抗体对小鼠神经毒性死亡具有保护活性,但抗NS 1抗体的作用
关于DV感染的更多相关外周组织从未被表征。然而,NS 1
包括在几种正在开发的DV疫苗中,包括我们的合作者夏威夷生物技术公司,
并且没有测试存在来评估由自然感染或疫苗接种产生的Ab的库(repertoire)。我们
已经表明,干扰素受体缺陷小鼠的DV感染再现了人DV的关键特征
感染,包括对所有四种DV血清型的易感性以及相关的感染动力学,适当的组织
和细胞嗜性,sNS 1在血液中的循环,血小板减少症与病毒载量相关,
血管渗漏综合征我们将使用这种小鼠模型来研究sNS 1的功能以及
抗NS 1抗体对DV感染的抑制作用。我们还将使用从小鼠获得的血清,
尼加拉瓜,和登革热疫苗试验,以产生体外测定,以评估抗NS 1抗体的库,
感染的小鼠、原发性和继发性自然DV感染和疫苗接受者。在具体目标1中,
将评估sNS 1在DV感染小鼠和致死性人类登革热病例中的定位和功能。
在特定目标2中,将评价抗NS 1 Ab对小鼠外周DV感染的影响。我们将
使用抗NS 1的多克隆Ab和抗NS 1的单克隆Ab和抗NS 1的单克隆Ab测量抗DV感染的能力,
NS 1疫苗接种和抗DV 2 NS 1的单克隆抗体,我们将筛选NS 1的任何有害的体内效应
ABS.最后,在特异性目的3中,我们将描述DV感染产生的抗NS 1抗体库
和疫苗接种,并将开发体外测试,以检测人血清中的抗NS 1抗体,
在随后的DV感染中的保护性或致病性作用。总之,这些结果将阐明
研究DV的致病机制,有助于开发安全有效的登革疫苗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 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:
$ 29.53万 - 项目类别:
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