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.
|Leiva-JuÃ¡rez, Miguel M; Ware, Hayden H; Kulkarni, Vikram V et al. (2016) Inducible epithelial resistance protects mice against leukemia-associated pneumonia. Blood 128:982-92|