Contribution of IL-1RI Signaling to Protection against Cryptococcus neoformans 52D in a Mouse Model of Infection

lnterleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that are induced after Cryptococcus neoformans infection and activate the interleukin-1 receptor type I (IL-1RI). To establish the role of IL-1RI signaling in protection against cryp-tococcal infection, we analyzed wild-type (WT) and IL-1RI-deficient (IL-1RI(-/-)) mice on the BALB/c background. IL-1RI(-/-) mice had significantly reduced survival compared to WT mice after intratracheal challenge with C. neoformans 52D. Microbiological analysis showed a significant increase in the lung and brain fungal burden of IL-1RI(-/-) compared to WT mice beginning at weeks 1 and 4 postinfection, respectively. Histopathology showed that IL-1RI(-/-) mice exhibit greater airway epithelial mucus secretion and prominent eosinophilic crystals that were absent in WT mice. Susceptibility of IL-1RI(-/-) mice was associated with significant induction of a Th2-biased immune response characterized by pulmonary eosinophilia, M2 macrophage polarization, and recruitment of CD4(+) IL-13(+) T cells. Expression of pro-inflammatory [IL-1 alpha, IL-1 beta, TNF alpha, and monocyte chemoattraetant protein 1 (MCP-1)], Th1-associated (IFN gamma), and Th 17-associated (IL-17A) cytokines was significantly reduced in IL-1RI(-/-) lungs compared to WT. WT mice also had higher expression of KC/CXCL1 and sustained neutrophil recruitment to the lung; however, antibody-mediated depletion of these cells showed that they were dispensable for lung fungal clearance. In conclusion, our data indicate that IL-1RI signaling is required to activate a complex series of innate and adaptive immune responses that collectively enhance host defense and survival after C. neoformans 52D infection in BALB/c mice.