Dual oxidase and lactoperoxidase in influenza infection

流感感染中的双氧化酶和乳过氧化物酶

• 批准号: 10328261
• 负责人: Balazs Rada
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-19 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328261
• 关键词: Affect; Animal Model; Anions; Antibody titer measurement; Antiviral Agents; Attenuated; Biological Models; Biology; Birds; Cell-Free System; Cells; Cysteine; Data; Economic Burden; Enzymes; Epithelial Cells; Future; Goals; Hemagglutinin; Human; Hydrogen Peroxide; Immune; Immune system; Impairment; In Vitro; Influenza; Influenza A virus; Influenza B Virus; Innate Immune Response; Intervention; Knowledge; Leukocytes; Link; Liquid substance; Lung; Lung infections; Measures; Mission; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Mouse Strains; Mus; NADPH Oxidase; Natural Immunity; Neuraminidase inhibitor; Outcome; Oxidases; Oxides; Participant; Pathogenesis; Pathogenicity; Patients; Persons; Proteins; Public Health; Pulmonary Inflammation; Pulmonary Pathology; Research; Resistance; Role; Route; Source; System; Testing; Therapeutic; Thiocyanates; United States National Institutes of Health; Vaccination; Viral; Viral Drug Resistance; Virion; Virus; Virus Diseases; Virus Inactivation; Virus Replication; Work; adaptive immune response; adaptive immunity; airway epithelium; airway surface liquid; anti-influenza; antimicrobial; apical membrane; attenuation; base; bronchial epithelium; cytokine; design; extracellular; fighting; human disease; hypothiocyanite; improved; in vitro testing; in vivo; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; innate immune mechanisms; innovation; lung injury; mortality; mouse model; novel; novel therapeutics; prevent; recruit; resistant strain; response; virucide; weapons

Project summary description Influenza virus infections affect millions of people worldwide every year and cause serious mortality. Current treatment options are limited to viral strain-specific vaccination and are problematic due to antiviral drug resistance. There is an urgent need to identify novel host innate immune mechanisms providing broad range protection against influenza. Bronchial epithelial cells orchestrate an oxidative extracellular antimicrobial system present in the airway surface liquid consisting of the protein lactoperoxidase (LPO), the thiocyanate anion (SCN- ) and hydrogen peroxide (H2O2). LPO oxidizes SCN- using H2O2 into hypothiocyanite (OSCN-) that has known in vitro antiviral effects. Dual oxidase 1 (Duox1), an NADPH oxidase highly expressed in bronchial epithelial cells, is the H2O2 source for the system. Our long-term goal is to determine whether the Duox1/H2O2/LPO/SCN- antiviral system could be manipulated in influenza infection for therapeutic purposes in human patients. The objective of this proposal is to determine and characterize the antiviral role of Duox1 and LPO against influenza in multiple experimental systems. Our preliminary data show that 1) primary bronchial epithelial cells inactivate several influenza viruses in an Duox1/H2O2/LPO/SCN- -dependent manner, 2) Duox1-deficient mice have increased mortality and morbidity, impaired viral clearance and leukocyte recruitment following influenza infection in vivo, and 3) the in vitro influenza-inactivating effect of this mechanism can be enhanced to inhibit influenza infection. Based on these data, our central hypothesis is that the Duox1/H2O2/LPO/SCN- system attenuates influenza infection, both in vitro and in vivo, and can be boosted to fight influenza. The rationale for the proposed research is that there is a need to better understand how powerful the antiviral Duox1/LPO-based system is and how can it be manipulated for therapeutic purposes. The main hypothesis will be tested in cell- free, airway epithelial and mouse model systems using a wide range of influenza strains. It is anticipated that our aims will yield several impactful outcomes including 1) detailed description of the anti-influenza mechanism of action of the Duox1/H2O2/LPO/SCN- system; 2) determination of the in vivo relevance of Duox1 in fighting a wide range of influenza strains; and 3) exploring the therapeutic potential of the Duox1/H2O2/LPO/SCN- system to improve influenza clearance and to diminish associated lung damage. Our innovative work shows that the Duox1/H2O2/LPO/SCN- system inactivates influenza, and uses a Duox1-deficient mouse strain for in vivo studies. The significance of the outlined work relies in establishing the relevance of a novel innate immune mechanism of the airways that can be enhanced to attenuate influenza infections or applied in conjunction with influenza vaccines to potentially enhance efficacy. In summary, our proposed work will have a positive impact in the fields of airway epithelial biology and antiviral innate immune responses by identifying Duox1 and LPO, as novel, crucial weapons of the bronchial epithelium against influenza.

项目摘要说明 流感病毒感染每年都会影响全球数百万人，并导致严重的死亡。 当前的治疗选择仅限于病毒菌株特异性疫苗接种，由于抗病毒药物而存在问题 反抗。迫切需要确定新型宿主先天免疫机制，提供广泛的范围 防止流感。支气管上皮细胞协调氧化性细胞外抗菌系统 存在于由蛋白质乳糖氧化酶（LPO）组成的气道表面液体中 ）和过氧化氢（H2O2）。 LPO使用H2O2将SCN-氧化成在众所周知 体外抗病毒作用。双氧化酶1（DUOX1），一种在支气管上皮细胞中高表达的NADPH氧化酶， 是系统的H2O2源。我们的长期目标是确定DUOX1/H2O2/LPO/SCN-是否是否 在人类患者的治疗目的中，可以在流感感染中操纵抗病毒系统。这 该建议的目的是确定和表征DUOX1和LPO对流感的抗病毒作用 在多个实验系统中。我们的初步数据表明1）原发支气管上皮细胞失活 DUOX1/H2O2/LPO/SCN-依赖性方式中的几种流感病毒，2）DUOX1缺陷小鼠具有 流感后的死亡率和发病率提高，病毒清除率受损和白细胞募集 体内感染和3）该机制的体外流感灭活作用可以增强以抑制 流感感染。基于这些数据，我们的中心假设是DUOX1/H2O2/LPO/SCN-系统 体外和体内的流感感染减弱，可以促进与流感融合。理由 拟议的研究是，有必要更好地了解抗病毒DUOX1/LPO的强大程度 系统是为了治疗目的，如何操纵它。主要假设将在细胞中检验 使用多种流感菌株的免费，气道上皮和小鼠模型系统。预计 我们的目标将产生几个有影响力的结果，包括1）抗激素机制的详细描述 DUOX1/H2O2/LPO/SCN-系统的作用； 2）确定Duox1在与A战斗中的体内相关性 广泛的流感菌株； 3）探索DUOX1/H2O2/LPO/SCN-系统的治疗潜力 提高流感清除率并减少相关的肺部损伤。我们的创新工作表明 DUOX1/H2O2/LPO/SCN-系统使流感失活，并使用DUOX1缺陷型小鼠菌株进行体内研究。 概述作品的重要性依赖于建立新型先天免疫机制的相关性 可以增强的气道减轻流感感染或与流感一起应用 疫苗有可能增强功效。总而言之，我们拟议的工作将对该领域产生积极影响 气道上皮生物学和抗病毒先天免疫反应，通过识别DUOX1和LPO为新颖 支气管上皮的关键武器针对流感。