β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 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 T(H)2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with beta-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed T(H)2 and T(H)17 responses, including IL-13(+)IL-17(+)CD4(+) double- producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc 2/2 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.