Duox2 Modulation of Viral Infection in Airway Epithelium

Duox2 调节气道上皮病毒感染

• 批准号: 8215722
• 负责人: Richart W Harper
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215722
• 关键词: Acids; Acute; Address; Antiviral Agents; Antiviral Response; Apical; Asthma; Biometry; Center for Translational Science Activities; Clinical Sciences; Consult; Critiques; Epithelial Cells; Epithelium; Event; Generations; Genes; Head; Health Sciences; Host Defense; Hour; Human; Hydrogen Peroxide; Infection; Interferons; Interleukin-13; Interleukin-4; Knowledge; Lung; Mediating; Modeling; Patients; Principal Investigator; Production; Proteins; Public Health; Reactive Nitrogen Species; Respiratory System; Respiratory tract structure; Rhinovirus; Services; Signal Pathway; System; Testing; Time; Up-Regulation; Viral; Virus Diseases; airway epithelium; asthmatic patient; cytokine; novel; pathogen; professor; programs

DESCRIPTION (provided by applicant): Rhinovirus (RV) is an important pathogen present in the respiratory tract epithelium of a significant proportion of asthma patients during severe pulmonary exacerbations. Mechanisms by which the human respiratory tract epithelium identifies acute RV infection, mechanisms used immediately by the human respiratory tract epithelium to respond to this infection, and how these mechanisms are impaired in asthmatics have not been fully elucidated. Our recent studies of DUOX2 suggest this protein is critical for normal antiviral host defense. We hypothesize that DUOX2 is a central component for host defense against RV infection in respiratory tract epithelium: When activated by RV, DUOX2 produces hydrogen peroxide (H2O2), hypohalous acid, or reactive nitrogen species to (a) directly inactivate rhinovirus and (b) stimulate the expression of early antiviral genes, but (c) antiviral activity is suppressed in the presence of Th2 cytokines such as interleukin-4 (IL- 4) or interleukin-13 (IL-13). Specific Aims: Test the predictions that (1) DUOX2-mediated generation of H2O2, hypohalous acids, or reactive nitrogen species directly inactivates RV, (2) DUOX2- mediated generation of H2O2 results in the early activation of antiviral genes, and (3) IL-4 blocks DUOX2-mediated antiviral activity by inhibiting transcriptionally-mediated DUOX2 expression. We will use human respiratory tract epithelial cells for all the studies outlined for this project. Relevance to Public Health - Rhinovirus (RV) is an important pathogen present in the respiratory tract epithelium of a significant proportion of asthma patients during severe pulmonary exacerbations. Our recent studies of DUOX2 suggest this protein is critical for normal antiviral host defense. We anticipate our studies will reveal novel mechanisms by which the respiratory tract epithelium activates innate host defense against RV infection. These studies will potentially elucidate specific mechanisms that are impaired in asthmatic patients.

描述（由申请人提供）：鼻病毒（RV）是在严重肺部恶化期间大部分哮喘患者的呼吸道上皮中存在的重要病原体。人类呼吸道上皮鉴定急性RV感染的机制，人呼吸道上皮立即使用以应对这种感染的机制，以及在哮喘患者中如何损害这些机制。我们最近对DUOX2的研究表明，该蛋白对于正常的抗病毒宿主防御至关重要。 We hypothesize that DUOX2 is a central component for host defense against RV infection in respiratory tract epithelium: When activated by RV, DUOX2 produces hydrogen peroxide (H2O2), hypohalous acid, or reactive nitrogen species to (a) directly inactivate rhinovirus and (b) stimulate the expression of early antiviral genes, but (c) antiviral activity is suppressed in the presence of Th2细胞因子，例如白介素4（IL-4）或白介素13（IL-13）。具体目的：测试（1）DUOX2介导的H2O2，低孔酸或反应氮的产生直接失活的RV，（2）DUOX2-介导的H2O2产生H2O2导致早期激活抗病毒基因的早期激活，（3）IL-4阻断DUOX2 DUOX2介导的抗激发作用，并通过抗激发作用进行了抗激活，并通过抗激发作用进行了抗激活。我们将使用人类呼吸道上皮细胞进行该项目概述的所有研究。与公共卫生 - 鼻病毒（RV）相关的是，在严重的肺部恶化期间，大部分哮喘患者的呼吸道上皮中存在重要的病原体。我们最近对DUOX2的研究表明，该蛋白对于正常的抗病毒宿主防御至关重要。我们预计我们的研究将揭示新的机制，通过这种机制，呼吸道上皮会激活对RV感染的先天宿主防御。这些研究可能会阐明哮喘患者受损的特定机制。

项目成果

DUOX-Mediated Signaling Is Not Required for LPS-Induced Neutrophilic Response in the Airways.

LPS 诱导的气道中性粒细胞反应不需要 DUOX 介导的信号传导。

• DOI: 10.1371/journal.pone.0131810
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chang,Sandra;Linderholm,Angela;Harper,Richart
• 通讯作者: Harper,Richart

Progressive cervical myelopathy as presentation of sarcoidosis.

进行性脊髓型颈椎病表现为结节病。

• DOI: 10.1007/s11606-012-2315-y
• 发表时间: 2013
• 期刊: Journal of general internal medicine
• 影响因子: 5.7
• 作者: Price,David;Harper,Richart;Henderson,MarkC
• 通讯作者: Henderson,MarkC

Immunobiology of the critical asthma syndrome.

• DOI: 10.1007/s12016-013-8407-6
• 发表时间: 2015-03
• 期刊: Clinical reviews in allergy & immunology
• 影响因子: 9.1
• 作者: Harper RW;Zeki AA
• 通讯作者: Zeki AA

Dual oxidase 2 bidirectional promoter polymorphisms confer differential immune responses in airway epithelia.

双氧化酶 2 双向启动子多态性赋予气道上皮细胞不同的免疫反应。

• DOI: 10.1165/rcmb.2012-0037oc
• 发表时间: 2012
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Xu,Changhong;Linderholm,Angela;Grasberger,Helmut;Harper,RichartW
• 通讯作者: Harper,RichartW

Dual oxidase regulates neutrophil recruitment in allergic airways.

• DOI: 10.1016/j.freeradbiomed.2013.06.012
• 发表时间: 2013-12
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Chang, Sandra;Linderholm, Angela;Franzi, Lisa;Kenyon, Nicholas;Grasberger, Helmut;Harper, Richart
• 通讯作者: Harper, Richart