Duox2 Modulation of Viral Infection in Airway Epithelium

描述(申请人提供)：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的严重肺加重期间的呼吸道上皮中。人类呼吸道上皮细胞识别急性轮状病毒感染的机制，人类呼吸道上皮细胞立即用来应对这种感染的机制，以及这些机制在哮喘患者中是如何受损的，还没有完全阐明。我们最近对DUOX2的研究表明，该蛋白对正常的抗病毒宿主防御至关重要。我们假设DUOX2是宿主抵抗呼吸道上皮RV感染的中心成分：当被RV激活时，DUOX2产生过氧化氢(H2O2)、次卤酸或反应性氮物种，以(A)直接灭活鼻病毒，(B)刺激早期抗病毒基因的表达，但(C)抗病毒活性在Th2细胞因子如白介素4(IL-4)或白介素13(IL-13)的存在下被抑制。具体目的：验证以下预测：(1)DUOX2介导的过氧化氢、次卤酸或活性氮物种的产生直接灭活轮状病毒，(2)DUOX2介导的过氧化氢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DUOX2表达来阻断DUOX2介导的抗病毒活性。我们将使用人类呼吸道上皮细胞进行这个项目概述的所有研究。与公共卫生相关-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的严重肺加重期间的呼吸道上皮中。我们最近对DUOX2的研究表明，该蛋白对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呼吸道上皮激活针对轮状病毒感染的天然宿主防御的新机制。这些研究可能会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.