Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

causes deadly mycosis primarily in AIDS patients, whereas infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome of and infections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. In infected mice, pICLC activity was associated with containment and classical Th1 immunity. In contrast, pICLC activity against did not require any immune factors previously associated with immunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly, pICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggesting pICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcus , suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection by and but by distinct mechanisms; the effect was mediated by iron limitation, while the effect on infection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for different species suggests a possible mechanism by which HIV infection may select against but not and cause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species, infects very few AIDS patients, while infection is an AIDS-defining illness, suggesting that the host response to HIV selects over We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action against was due to activation of well-defined immune pathways known to deter , whereas these immune pathways were dispensable for pICLC treatment of Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to control infection but is protective against Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibited , thus suggesting an entirely new mode of nutritional immunity activated by viral signals.