Exogenous induction of type I IFN protects mice from Cryptococcus neoformans and Cryptococcus gattii infections by cellular immunity and iron restriction.

Abstract

Abstract Rational Cryptococcus neoformans (Cn) causes deadly mycosis in AIDS patients whereas Cryptococcus gattii (Cg) infects mostly non-HIV patients. 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 mortality with reduced fungal burdens. In Cn infected mice, PIC protection was mediated by classical Th1 immunity as CD4 T cells and IFNγ were required and Cn mediated Th2 polarization and eosinophilia were reversed by PIC. In contrast, PIC protection from Cg did not require any of the immune factors previously associated with Cn immunity; T cells, B cells, NK cells, IFNγ and monocyte derived myeloid cells were all dispensable for protection. Interestingly, PIC protection depended on β-2-microglobulin (B2m). In addition to its role as a co-factor for several immunological proteins, B2m is involved in iron trafficking suggesting that PIC protection may function by limiting Cg’s access to iron. In support of this, iron supplementation reversed PIC protection and iron chelation mediated similar protection as PIC. PIC also induced expression of several proteins involved in iron trafficking. Conclusions These data show that t1I induction protects mice from Cn and Cg but protection was mediated by distinct immune mechanisms. PIC mediated protection from Cn requires CD4 T cells and IFNγ. However, this classical immune pathway to cryptococcosis is not involved in PIC-mediated protection from Cg. Instead, PIC protection from Cg seems to involve iron limitation suggesting a novel role for t1I in regulating host iron in the lungs.