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中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。相反，免疫抑制疗法增强了病毒的易感性。肺上皮细胞是大多数呼吸道病毒的主要靶点，对哮喘发病至关重要，也是清除呼吸道病毒所必需的。最近的研究表明，肺上皮细胞可以通过治疗性刺激来广泛地预防肺炎，包括病毒感染。因此，假设在肺部唤起保护性的局部抗病毒免疫反应，而不是不分青红皂白地抑制所有炎症，将防止哮喘恶化并减少进展。尽管有过敏性炎症，但对病毒的诱导抗性仍然存在，并且在不加剧气道高反应性或粘膜化生的情况下保护病毒。然而，所有炎症都对哮喘患者有害这一根深蒂固的观点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转化。除了量化该策略在预防病毒诱导的小鼠哮喘方面的功效外，该应用还提出了利用遗传、药理学和体外工具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治疗的临床递送。其次，诱导抗病毒保护所需的近端信号分子将被识别，允许解剖

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.