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

Abstract

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

A New Lineage of Cryptococcus gattii (VGV) Discovered in the Central Zambezian Miombo Woodlands

“…Previous work has shown that most isolates of the C. gattii species complex cause pulmonary infection in a murine model with low neurotropism (20,40,41). The four VGV isolates tested here were less neurotropic than the MF46 VGIV isolate that was collected from the same Zambian environment, and all the examined Zambian envi-ronmental isolates were significantly less virulent than a VGIV control strain, WM779.…”

MDA5 Is an Essential Sensor of a Pathogen-Associated Molecular Pattern Associated with Vitality That Is Necessary for Host Resistance against Aspergillus fumigatus

“…**p , 0.01. hpi, hour postinoculation. poly(I:C) drove type I IFN expression and iron limitation, which corresponded with improved disease outcomes (96,97). However, opposing roles of type I IFN signaling in T cell polarization following C. neoformans challenge have been observed, either promoting protective Th1 cells (98) or nonprotective Th2 cells (99).…”

The role of Toll-like receptor 9 in a murine model of Cryptococcus gattii infection

“…The cytokines produced by Th1 are essential for immunity and the cytokines associated with the Th2 profile do not provide protection. It is well described in the literature that the increase in IFN-γ production is related to protection against cryptococcosis, inducing an increase in phagocytic activity and fungicidal activity of phagocytes, favoring the host's response to infection control 47,48 . In an experimental model using an IFN-γproducing C. neoformans strain, the authors observed reduced pulmonary fungal burden, classical macrophage activation, Th1 pulmonary response and IL-17 production 49 .…”