title: Phenotypic switching in Cryptococcus neoformans contributes to virulence by changing the immunological host response.
abstract: 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.
authors.affiliation: Departments of Microbiology and Immunology, Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Guerrero
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Fries
mesh_terms: D000818:Animals; D000940:Antigenic Variation / Q000276:immunology* / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000472:pathogenicity*; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D005260:Female; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000737:chemistry / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016019:Survival Analysis; D014774:Virulence
chemical_list: D016207:Cytokines; D016753:Interleukin-10