β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant T_H2/T_H17 responses.

Abstract

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. We sought to determine the mechanism by which fungi affect asthma development and severity. We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. We report that fungal exposure enhances allergen-driven T_H2 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 T_H2 and T_H17 responses, including IL-13⁺IL-17⁺CD4⁺ double-producing effector T cells. Steroid resistance is dependent on fungus-induced T_H17 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. 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.