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

Abstract

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