Type I Ifn Induces Vascular Permeability Delivering Iron Binding Proteins To The Site Of Cryptococcosis Gattli Infection Resulting In Local Nutritional Immunity And Contained Infection

Abstract While Cryptococcus neoformans primarily infect AIDS patients, Cryptococcus gattii (Cg) causes deadly mycosis in mostly non-HIV patients even in Cg endemic areas with high rates of AIDS. Previous work found that type I IFN (t1IFN), which is induced by HIV infection, protects mice from Cg. Thus, we sought to examine the mechanisms mediating t1IFN protection from Cg. Previous data ruled out cellular immunity, so we examined soluble immune factors. We found that induction of t1IFN by stabilized poly(I:C) (pICLC) induced the expression of serum proteins into the lung airspace fluids. PICLC induced the leak of intravenously injected FITC-dextran into lung airspace fluids suggesting that serum proteins reach the lung airspace via t1IFN-induced vascular permeability. The pICLC-mediated expression of serum proteins into the lung airspace was dependent on t1IFN but not IL-6, IL-1 or TNF-α indicating that this effect is mediated by t1IFN and not by other cytokines characterized to affect vascular permeability. Transferrin and ferritin were among the leaked serum proteins found in the lung airspace and were directly inhibitory to cryptococcus in vitro so we hypothesized that the presence of these proteins in the lung airspace may result in local iron deficiency. Iron supplementation reversed pICLC-protection while iron chelation mediated similar protection as pICLC. Together these data suggest that t1IFN induces vascular permeability in the lung which delivers iron binding proteins to the Cg niche. These host proteins restrict iron to Cg and limit infection. In addition to explaining the pICLC-induced protection from Cg, these studies illustrate a novel connection between t1IFN and vascular permeability that may be significant to other systems.