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Infect. Immun. doi:10.1128/IAI.00529-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

Departments of Microbiology and Immunology, and Medicine at Albert Einstein College of Medicine, Bronx, New York 10461

^* To whom correspondence should be addressed. Email: fries{at}aecom.yu.edu.

	Abstract

Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process the parent Smooth (SM) colony switches to a more virulent mucoid (MC) colony variant. The host response mounted against the SM and MC variants differs and lower tissue levels of IL-10 are consistently observed in lungs of MC infected C57BL/6 and BALB/c mice. This suggested a different role of this cytokine in SM and MC infection. The objective of this study was to compare survival and characterize the host response of SM and MC infected IL-10 depleted mice (IL-10-/-), 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 response of SM and MC infected IL-10-/- and wild-type mice. This included a more Th₁ polarized inflammatory response with enhanced recruitment of macrophages, natural killer and CD8 cells in MC when compared to 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, TGF-beta, IL-12 and IFN-gamma were higher in MC infected IL-10-/- and wild-type mice relative to SM infected mice whereas TNF-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 outcome is negatively affected by the absence of IL-10.