Iron Source Preference and Regulation of Iron Uptake in Cryptococcus neoformans

Abstract

The level of available iron in the mammalian host is extremely low, and pathogenic microbes must compete with host proteins such as transferrin for iron. Iron regulation of gene expression, including genes encoding iron uptake functions and virulence factors, is critical for the pathogenesis of the fungus Cryptococcus neoformans. In this study, we characterized the roles of the CFT1 and CFT2 genes that encode C. neoformans orthologs of the Saccharomyces cerevisiae high-affinity iron permease FTR1. Deletion of CFT1 reduced growth and iron uptake with ferric chloride and holo-transferrin as the in vitro iron sources, and the cft1 mutant was attenuated for virulence in a mouse model of infection. A reduction in the fungal burden in the brains of mice infected with the cft1 mutant was observed, thus suggesting a requirement for reductive iron acquisition during cryptococcal meningitis. CFT2 played no apparent role in iron acquisition but did influence virulence. The expression of both CFT1 and CFT2 was influenced by cAMP-dependent protein kinase, and the iron-regulatory transcription factor Cir1 positively regulated CFT1 and negatively regulated CFT2. Overall, these results indicate that C. neoformans utilizes iron sources within the host (e.g., holo-transferrin) that require Cft1 and a reductive iron uptake system.

The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host

“…Rim101 has also been implicated in the regulation of iron and copper homeostasis both in C. neoformans and in other fungal species (24,34,35,53). Therefore, we examined the Rim101 binding of the promoters of the HAPX, CTR4, and CFT1 genes (Fig.…”

Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

“…Interestingly, CD4C/HIV Nef transgenic mice display increased circulating ferritin levels due to Nef-dependent release of ferritin from macrophages, and plasma ferritin levels are correlated with viral RNA in HIV-1-infected patients (68). C. neoformans can acquire iron bound to the major carrier transferrin by a reductive iron uptake pathway (69). Because growth of C. neoformans at high iron concentrations results in cells with thinner capsules (30) and lower expression of the CAP60 gene that is required for capsule production (70), increased availability of iron from the ferritin carrier may have contributed to the lack of capsule thickening during the course of cryptococcal infection in the Tg mice.…”

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

“…Previously, a connection between iron availability and antifungal drug susceptibility was observed in C. neoformans, S. cerevisiae, and Candida spp. (7,8,37,38,39). In C. neoformans, loss of CFO1 and CFT1 (high-affinity iron uptake components) resulted in increased susceptibility to azole as well as polyene drugs.…”

“…The cell wall mannoproteins Cig1 (in C. neoformans) and Rbt5 and Rbt51 (in C. albicans), as well as the heme oxygenase Hmx1 (in C. albicans), are involved in acquiring iron from heme (6)(7)(8)(9)(10)(11). The reductive high-affinity iron uptake system is an important virulence determinant in C. neoformans and C. albicans but not in A. fumigatus, and this mechanism is employed by these two pathogens to acquire iron from transferrin in mammalian hosts (7,8,12). This iron uptake system involves the reduction of ferric iron to ferrous iron by cell surface reductases, followed by ferrous iron oxidation by a ferroxidase coupled to an iron permease for transport.…”