IL-22 Promotes IFN-γ-Mediated Immunity against Histoplasma capsulatum Infection

Histoplasma capsulatum is the agent of histoplasmosis, one of the most frequent mycoses in the world. The infection initiates with fungal spore inhalation, transformation into yeasts in the lungs and establishment of a granulomatous disease, which is characterized by a Th1 response. The production of Th1 signature cytokines, such as IFN-gamma, is crucial for yeast clearance from the lungs, and to prevent dissemination. Recently, it was demonstrated that IL-17, a Th17 signature cytokine, is also important for fungal control, particularly in the absence of Th1 response. IL-22 is another cytokine with multiple functions on host response and disease progression. However, little is known about the role of IL-22 during histoplasmosis. In this study, we demonstrated that absence of IL-22 affected the clearance of yeasts from the lungs and increased the spreading to the spleen. In addition, IL-22 deficient mice (Il22(-/-)) succumbed to infection, which correlated with reductions in the numbers of CD4(+) IFN-gamma(+) T cells, reduced IFN-gamma levels, and diminished nitric oxide synthase type 2 (NOS2) expression in the lungs. Importantly, treatment with rIFN-gamma mitigated the susceptibility of Il22(-/-) mice to H. capsulatum infection. These data indicate that IL-22 is crucial for IFN-gamma/NO production and resistance to experimental histoplasmosis.