Exogenous induction of type I IFN protects mice from Cryptococcus neoformans and Cryptococcus gattii infections by distinct CD4+ T cell and CD8+ T cell-mediated mechanisms.

Abstract

Abstract Rational Cryptococcus neoformans (Cn) causes deadly mycosis in AIDS patients whereas the Vancouver outbreak strain of Cryptococcus gattii (Cg) mostly infects otherwise healthy individuals but not AIDS patients even where the strains are equally prevalent in the environment. As HIV infection induces type I IFN (t1I) we hypothesized that exogenously induced t1I would differentially affect infections by Cn and Cg. Results Cn or Cg infected mice were dosed with poly(I:C)LC (PIC) to induce t1I. PIC-treated mice were protected from Cn and Cg infection-mediated death with reduced fungal burdens. Both Cn and Cg infection produced a non-protective immune response dominated by Th2 cell recruitment, M2/DC2 polarization and eosinophilia. PIC-treatment reversed the Th2 polarization toward increased Th1/17 cells, M1/DC1 polarization and reduced eosinophilia. PIC also induced activation of CD8 T cells in both Cg and Cn infected mice. Cg-infected CD8 cell-deficient mice were not protected by PIC treatment while PIC protection was intact in Cn-infected CD8 cell-deficient mice. In contrast, PIC protection was intact in Cg-infected CD4 cell-deficient mice while Cn-infected CD4 cell-deficient mice were not protected by PIC treatment. Conclusions These data show that t1I induction protects mice from Cn and Cg however protection was mediated by distinct immune mechanisms. PIC-mediated protection from Cn requires CD4 but not CD8 cells while PIC-mediated protection from Cg requires CD8 but not CD4 cells. Notably, Cn but not Cg was able to grow in CD4-deficient t1I-induced mice, which somewhat resemble the immunological condition of AIDS patients, suggesting a novel explanation for the observed AIDS patient tropism of these cryptococcal species.