Pathogenesis of Acute Respiratory Diseases: SARS and INFLUENZA
急性呼吸道疾病的发病机制:SARS 和流感
基本信息
- 批准号:8609326
- 负责人:
- 金额:$ 32.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Factors implicated in high morbidity and mortality following influenza, SARS, Hanta and Ebola virus infection
include robust cytokine production (cytokine storm), excessive inflammatory infiltrates (immunopathology),
and virus-induced tissue destruction. Our studies with pathogenic human H1N1 influenza virus (Cell 146,
2011; PNAS 108, 2011) were the first to definitively show that cytokine storm causes, rather than associates
with resultant morbidity and mortality. Infection occurs in epithelial cells and cytokine storm is initiated and
amplified by pulmonary endothelial cells. Modulation of sphingosine-1-phosphate (S1P)1 receptor on
pulmonary endothelial cells curtails early innate immune responses and protects the infected host
significantly better (82%) than antiviral compounds (50%) while usage of antiviral therapy combined with
S1P agonists afford optimal protection (96%). We demonstrated that cytokine production and leukocyte
recruitment are independent occurrences, and S1P1 receptor signaling on pulmonary endothelial cells
regulates both events. We uncovered that cytokine amplification depends on type 1 interferon signaling. The
MRCE with its collection of investigators with interests and experience in innate immune pathways and type
1 interferon signaling provide a synergism with our proposal. Our goal is to understand how cytokine
amplification is regulated. Specifically, how type 1 interferon regulates global cytokine amplification following
human pandemic H1N1/2009 influenza infection. We will determine if a similar amplification loop exists in
SARS infection for which preliminary evidence shows is successfully modified by S1P therapy. Our specific
aims make use of currently on hand reagents to determine the subset(s) of interferon required to amplify
early cytokine production, lineage tracing reporter Td-tomato and IFNAR1flox/flox mice to identify the
specific cell subsets responsible for cytokine amplification and to analyze cross talk signaling pathways that
are important players in cytokine storm. The future fruits of our studies are aimed at both therapeutics to
control cytokine storm and markers to identify susceptible individuals to these diseases.
流感、SARS、汉他和埃博拉病毒感染后高发病率和死亡率的相关因素
包括强烈细胞因子产生(细胞因子风暴)、过度的炎性浸润(免疫病理学)
和病毒引起的组织破坏我们对致病性人H1N1流感病毒(细胞146,
2011年; PNAS 108,2011年)首次明确表明细胞因子风暴导致,而不是相关的
导致发病率和死亡率。感染发生在上皮细胞中,启动细胞因子风暴,
由肺内皮细胞放大。1-磷酸鞘氨醇(S1P)1受体对
肺内皮细胞减少早期先天免疫应答并保护感染宿主
与抗病毒化合物(50%)相比,
S1P激动剂提供最佳保护(96%)。我们证明了细胞因子的产生和白细胞
募集是独立发生的,肺内皮细胞上的S1P1受体信号传导
规范这两个事件。我们发现,细胞因子的扩增依赖于1型干扰素信号。的
MRCE及其收集的研究人员对先天免疫途径和类型感兴趣并有经验
1干扰素信号传导提供与我们的提议的协同作用。我们的目标是了解细胞因子
放大是有规律的。具体而言,1型干扰素如何调节以下细胞因子的整体扩增:
人类大流行性H1N1/2009流感感染。我们将确定是否存在类似的放大循环,
初步证据显示,S1P疗法成功地改变了SARS感染。我们的具体
目的是利用现有的试剂来确定扩增所需的干扰素亚群,
早期细胞因子的产生,谱系追踪报告Td-tomato和IFNAR1flox/flox小鼠,以鉴定
负责细胞因子扩增的特定细胞亚群,并分析
是细胞因子风暴的重要参与者。我们研究的未来成果旨在治疗,
控制细胞因子风暴和标记物,以识别对这些疾病易感的个体。
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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MICHAEL B OLDSTONE其他文献
MICHAEL B OLDSTONE的其他文献
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{{ truncateString('MICHAEL B OLDSTONE', 18)}}的其他基金
Host Genetic Factors to Combat Lassa Hemorrhagic Fever
对抗拉沙出血热的宿主遗传因素
- 批准号:
8573827 - 财政年份:2013
- 资助金额:
$ 32.47万 - 项目类别:
Host Genetic Factors to Combat Lassa Hemorrhagic Fever
对抗拉沙出血热的宿主遗传因素
- 批准号:
8711266 - 财政年份:2013
- 资助金额:
$ 32.47万 - 项目类别:
Host Genetic Factors to Combat Lassa Hemorrhagic Fever
对抗拉沙出血热的宿主遗传因素
- 批准号:
9118852 - 财政年份:2013
- 资助金额:
$ 32.47万 - 项目类别:
Novel Chemical and Immunological Approaches to Influenza Therapy
流感治疗的新化学和免疫学方法
- 批准号:
7288013 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
Novel Chemical and Immunological Approaches to Influenza Therapy
流感治疗的新化学和免疫学方法
- 批准号:
8076285 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
Novel Chemical and Immunological Approaches to Influenza Therapy
流感治疗的新化学和免疫学方法
- 批准号:
7864328 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
In Vivo Analysis of T lymphocytes in the Persistently Infected CNS
持续感染中枢神经系统中 T 淋巴细胞的体内分析
- 批准号:
7570017 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
Novel Chemical and Immunological Approaches to Influenza Therapy
流感治疗的新化学和免疫学方法
- 批准号:
7626430 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
Novel Chemical and Immunological Approaches to Influenza Therapy
流感治疗的新化学和免疫学方法
- 批准号:
7433177 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
In Vivo Analysis of T lymphocytes in the Persistently Infected CNS
持续感染中枢神经系统中 T 淋巴细胞的体内分析
- 批准号:
8026029 - 财政年份:2007
- 资助金额:
$ 32.47万 - 项目类别:
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