Phenotypic switching in Cryptococcus neoformans contributes to virulence by changing the immunological host response

Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10(-/-)) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM- infected IL-10(-/-) mice survived longer than wild-type mice, whereas MC-infected IL-10(-/-) mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10(-/-) and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC-than in SM- infected IL-10(-/-) and wild-type mice. In contrast, both SM- infected IL-10(-/-) and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10(-/-) and wild-type mice than in SM- infected mice, whereas tumor necrosis factor alpha levels were higher in SM- infected IL-10(-/-) mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.