IFN-alpha/beta signaling is required for polarization of cytokine responses toward a protective type I pattern during experimental cryptococcosis

The antiviral activities of type I IFNs have long been established. However, comparatively little is known of their role in defenses against nonviral pathogens. We examined here the effects of type I IFNs on host resistance against the model pathogenic yeast Cryptococcus neoformans. After intratracheal or i.v. challenge with this fungus, most mice lacking either the IFN-/ receptor (IFN-/R) or IFN- died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-/R/ mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-, IFN-, inducible NO synthetase, and CXCL10, and similar levels of IL-12 mRNA, compared with wild-type controls. Histopathological analysis showed eosinophilic infiltrates in the lungs of IFN-/R/ mice, although this change was less extensive than that observed in similarly infected IFN-R-deficient animals. Type I IFN responses could not be detected in the lung after intratracheal challenge. However, small, but statistically significant, elevations in IFN- levels were measured in the supernatants of bone marrow-derived macrophages or dendritic cells infected with C. neoformans. Our data demonstrate that type I IFN signaling is required for polarization of cytokine responses toward a protective type I pattern during cryptococcal infection.