Abstract
The fungal pathogen Cryptococcus neoformans is a major cause of illness in immunocompromised individuals such as AIDS patients. The ability of the fungus to acquire nutrients during proliferation in host tissue and the ability to elaborate a polysaccharide capsule are critical determinants of disease outcome. We previously showed that the GATA factor, Cir1, is a major regulator both of the iron uptake functions needed for growth in host tissue and the key virulence factors such as capsule, melanin and growth at 37°C. We are interested in further defining the mechanisms of iron acquisition from inorganic and host-derived iron sources with the goal of understanding the nutritional adaptation of C. neoformans to the host environment. In this study, we investigated the roles of the HAP3 and HAPX genes in iron utilization and virulence. As in other fungi, the C. neoformans Hap proteins negatively influence the expression of genes encoding respiratory and TCA cycle functions under low-iron conditions. However, we also found that HapX plays both positive and negative roles in the regulation of gene expression, including a positive regulatory role in siderophore transporter expression. In addition, HapX also positively regulated the expression of the CIR1 transcript. This situation is in contrast to the negative regulation by HapX of genes encoding GATA iron regulatory factors in Aspergillus nidulans and Schizosaccharomyces pombe. Although both hapX and hap3 mutants were defective in heme utilization in culture, only HapX made a contribution to virulence, and loss of HapX in a strain lacking the high-affinity iron uptake system did not cause further attenuation of disease. Therefore, HapX appears to have a minimal role during infection of mammalian hosts and instead may be an important regulator of environmental iron uptake functions. Overall, these results indicated that C. neoformans employs multiple strategies for iron acquisition during infection.
Highlights
The fungus Cryptococcus neoformans causes life-threatening illness in immunocompromised individuals
The sequence alignments, deletion constructs and confirmation of the mutant genotypes are shown in Figures S3 and S4. These results indicated that Hap3, Hap5 and HapX all contribute to iron utilization from hemin; this finding prompted a further examination of the impact of hap mutations on iron-related transcription and virulence
We demonstrated that the GATA factor Cir1 is a major regulator of both iron acquisition and virulence in C. neoformans [15]
Summary
The fungus Cryptococcus neoformans causes life-threatening illness in immunocompromised individuals. A related species, Cryptococcus gattii, has emerged as a primary pathogen of immunocompetent people, as demonstrated by the ongoing occurrence of infections in otherwise healthy people and animals on the West Coast of North America [2,3,4]. These fungi share a set of virulence determinants that include the production of a polysaccharide capsule, the formation of melanin in the cell wall and the ability to grow at 37uC. Melanin synthesis is regulated by iron and additional factors such as glucose [10,11,12]
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