β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH 2/TH 17 responses

Background Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. Objective We sought to determine the mechanism by which fungi affect asthma development and severity. Methods We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. Results We report that fungal exposure enhances allergen-driven TH 2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with β-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH 2 and TH 17 responses, including IL-13+ IL-17+ CD4+ double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH 17 responses because steroid sensitivity was restored in IL-17rc−/− mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. Conclusion Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma.