Interleukin-4 Causes Susceptibility to Invasive Pulmonary Aspergillosis through Suppression of Protective Type I Responses

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and non-allergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threat-ening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)±4±de®cient (IL-42/2) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-42/2 mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was as-sociated with decreased lung in¯ammatory pathology, impaired T helper (Th)±2 responses (including lung eosinophilia), and an IL-12±dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-122/2 and interferon-g2/2 mice and in IL-42/2 mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 re-sponses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus. Aspergillus fumigatus is a ubiquitous and opportunistic fun-gal pathogen of humans and animals. It is associated with