Study on the roles of IL-25 in regulating immune response to Cryptococcus infection

Cryptococcal meningitis caused by Cryptococcus infection is one of the most common life-threatening diseases observed worldwide. Accumulating evidence suggests that type-2 immune response that usually occurred within the lung after infection was associated with the progression of the disease by promoting growth and dissemination of the fungus. However, factors that underlie this pathogenic response during infection are still elusive. Thus, this study aimed to investigate the roles of IL-25, one of the type-2 inducing cytokines produced by epithelial cells, in contributing to the pathogenesis during Cryptococcus infection. Pulmonary infection of C. neoformans significantly induced the expression of IL-25 within the lungs at the chronic state. Mice deficient in interleukin-17 receptor B (IL-17RB), a component of the IL-25 receptor, exhibited a better survival coupled with a reduction of fungus within the brain. Moreover, C. neoformans infection in IL-17RB knockout mice resulted in an enhanced type-1 immune response and altered macrophage phenotype from pathogenic M2 to protective M1 phenotype within the lung. Although there was no change in the brain cellular inflammation and microglial cell activation, the increased expression of protective cytokines and chemokines including Ifng, Il1b, Ip10, and Nos2 was observed. Moreover, Il17rb-/- mice received of cryptococcal-specific CD4+ T cells from wild-type mice exhibited a shorter survival rate along with a higher fungal burden and induction of M2 macrophage markers within the brain than those received of cryptococcal-specific CD4+ T cells from Il17rb-/- mice. Altogether, these observations demonstrate that IL-25 signaling is required for the development of cryptococcal disease pathogenesis by subverting protective immunity and amplifying permissive type-2 immune response that facilitates growth and dissemination of C. neoformans to the central nervous system.