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佳的哮喘。由于嗜酸性和中性粒细胞炎症是疾病的特征，抗炎药物是治疗的主要药物，尽管它们不能延缓疾病的进展。病毒感染导致大多数病情恶化并导致哮喘进展，但并不是哮喘指南的目标。相反，免疫抑制疗法会增加病毒的易感性。肺上皮细胞是大多数呼吸道病毒的主要靶点，是哮喘发病机制的关键，也是呼吸道病毒清除所必需的。最近有研究表明，肺上皮细胞可以被治疗性刺激，以广泛预防利萨肺炎，包括病毒感染。因此，据推测，在肺部唤起保护性的局部抗病毒免疫反应，而不是不加选择地抑制所有炎症，将防止哮喘恶化并减缓进展。尽管有过敏性炎症，但对病毒的可诱导耐药性仍然存在，并在不加剧呼吸道高反应性或粘液化生的情况下保护机体免受病毒侵袭。然而，所有炎症都对哮喘患者有害这一根深蒂固的立场要求澄清抗病毒反应的机制，以促进这一挑战范式的策略的临床翻译。除了量化这一策略在预防病毒诱导的小鼠哮喘方面的有效性外，这项应用还建议使用遗传学、药理学和体外工具来揭示抗病毒耐药性的机制。首先，将确定保护所需的特定上皮细胞群，促进随后的机制研究和优化吸入疗法的临床应用。其次，将识别诱导抗病毒保护所需的近端信号分子，从而进行解剖。 以前未描述的协同信号事件和确定诱导保护的替代可用药物靶点。最后，信号级联将被追踪到最终的抗病毒效应分子。最近的实验数据和文献表明，抗病毒的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特别研究。该项目挑战了关于抗菌素反应中炎症的性质、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、抗病毒分子的特征和肺自由基来源的主流概念。总而言之，这些数据有望推动哮喘治疗新纪元的临床转化。

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.