Inducible epithelial antiviral resistance to prevent asthma

描述（由申请人提供）：越来越多的美国人患有控制不良的哮喘。由于嗜酸性粒细胞和嗜酸性粒细胞炎症是疾病的标志，抗炎药物是治疗的主要手段，尽管它们不能延缓疾病的进展。病毒感染引起大多数急性发作并导致哮喘进展，但在哮喘指南中没有针对性。相反，免疫抑制疗法增强病毒易感性。肺上皮细胞是大多数呼吸道病毒的主要靶标，是哮喘发病机制的关键，并且是呼吸道病毒清除所必需的。最近已经表明，肺上皮细胞可以被治疗性地刺激以广泛地保护免于致死性肺炎，包括病毒感染。因此，假设在肺中引起保护性局部抗病毒免疫应答，而不是不加选择地抑制所有炎症，将预防哮喘恶化并减少进展。尽管存在过敏性炎症，但诱导的病毒抗性已被证明持续存在，并保护免受病毒感染，而不会加剧气道高反应性或粘液化生。然而，所有炎症对哮喘患者都是有害的这一根深蒂固的观点要求阐明抗病毒反应的机制，以促进这一具有挑战性的策略的临床转化。除了量化这种策略在小鼠中预防病毒诱导的哮喘的功效之外，本申请还提出使用遗传学、药理学和体外工具揭示抗病毒抗性的机制。首先，将确定保护所需的特定上皮细胞群，促进后续的机制研究和优化吸入疗法的临床递送。第二，将鉴定诱导抗病毒保护所需的近端信号分子， 以前未描述的协同信号事件，并确定替代的可药用靶点诱导保护。最后，信号级联将被跟踪到最终的抗病毒效应分子。最近的实验数据和文献表明，杀病毒部分可能是活性氧或氮物种。因此，挥发性抗病毒分子的新机制将被专门研究。该项目挑战了关于抗菌反应中炎症的本质、保护性免疫在哮喘中的作用、抗病毒宿主反应所需的细胞、协调信号转导的基本概念、杀病毒分子的特征和肺自由基的来源的流行概念。总之，这些数据有望推动哮喘治疗新时代的临床转化。

DESCRIPTION (provided by applicant): Increasing millions of Americans suffer from poorly controlled asthma. Because eosinophilic and neutrophilic inflammation are hallmarks of disease, anti-inflammatory drugs are the mainstay of therapy, though they do not retard disease progression. Viral infections cause most exacerbations and result in asthma progression, yet are not targeted in asthma guidelines. Rather, immunosuppressive therapies enhance viral susceptibility. Lung epithelial cells are the primary targets of most respiratory viruses, are critcal to asthma pathogenesis, and are required for respiratory virus clearance. It has recently been shown that lung epithelial cells can be therapeutically stimulated to broadly protect against letha pneumonias, including viral infections. Accordingly, it is hypothesized that evoking a protective local antiviral immune response in the lungs, rather than indiscriminate suppression of all inflammation, will prevent asthma exacerbations and reduce progression. Inducible resistance to viruses has been shown to persist despite allergic inflammation and to protect against viruses without exacerbating airways hyperreactivity or mucous metaplasia. However, the deeply entrenched position that all inflammation is harmful to asthma patients demands that the mechanisms of the antiviral response be clarified, in order to promote the clinical translation of this paradigm-challenging strategy. In addition to quantifying the efficacy of this strategy for preventing virus-induced asthma in mice, this application proposes to reveal the mechanisms of antiviral resistance using genetic, pharmacologic and in vitro tools. First, the specific epithelia cell populations required for protection will be identified, facilitating subsequent mechanistic investigations and optimizing clinical delivery of inhaled therapies. Second, the proximal signaling molecules required to induce antiviral protection will be identified, allowing dissection of previously undescribed synergistic signaling events and identifying alternate druggable targets for inducing protection. Finally, the signaling cascade will be followed to the ultimate antiviral effector molecules. Recent experimental data and literature suggest that the virucidal moieties may be reactive oxygen or nitrogen species. So, novel mechanisms of volatile antiviral molecules will be specifically investigated. This project challenges prevailing concepts regarding the nature of inflammation in antimicrobial responses, the role of protective immunity in asthma, the cells required for antiviral host responses, cardinal concepts of coordinate signal transduction, the character of virucidal molecules and the source of lung free radicals. Together, these data are expected to promote clinical translation of a new era of asthma therapy.