Duox2 Modulation of Viral Infection in Airway Epithelium

描述（由申请方提供）：鼻病毒（RV）是一种重要的病原体，存在于严重肺部急性发作期间相当一部分哮喘患者的呼吸道上皮中。人类呼吸道上皮细胞识别急性RV感染的机制、人类呼吸道上皮细胞立即用于响应这种感染的机制以及这些机制如何在哮喘患者中受损尚未完全阐明。我们最近对DUOX 2的研究表明，这种蛋白质对于正常的抗病毒宿主防御至关重要。我们假设DUOX 2是呼吸道上皮中宿主防御RV感染的核心组分：当被RV激活时，DUOX 2产生过氧化氢（H2 O2）、次卤酸或活性氮物质，以（a）直接抑制鼻病毒和（B）刺激早期抗病毒基因的表达，但（c）在Th 2细胞因子如白细胞介素-4（IL- 4）或白细胞介素-13（IL-13）存在下，抗病毒活性受到抑制。具体目标：检验以下预测：（1）DUOX 2介导的H2 O2、次卤酸或活性氮物质的产生直接灭活RV，（2）DUOX 2介导的H2 O2产生导致抗病毒基因的早期激活，以及（3）IL-4通过抑制转录介导的DUOX 2表达阻断DUOX 2介导的抗病毒活性。我们将使用人类呼吸道上皮细胞进行本项目概述的所有研究。与公共卫生的相关性-鼻病毒（RV）是一种重要的病原体，存在于相当大比例的哮喘患者在严重肺部急性发作期间的呼吸道上皮中。我们最近对DUOX 2的研究表明，这种蛋白质对于正常的抗病毒宿主防御至关重要。我们预期我们的研究将揭示呼吸道上皮细胞激活先天宿主防御RV感染的新机制。这些研究将可能阐明哮喘患者受损的具体机制。

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.