Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 207, Issue 8, Pages 1339-1347Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit029
Keywords
Cryptococcus neoformans; extracellular mannoprotein; heme uptake; fungal pathogenesis; Rim101; pH; fungal hemophore
Categories
Funding
- National Institutes of Health [R01 AI053721]
- Canadian Institutes of Health Research [MOP-13234]
- University of British Columbia
- Province of British Columbia
- Burroughs Wellcome Fund
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Iron acquisition is critical for virulence of the human pathogenic fungus Cryptococcus neoformans. The cryptococcal transcript for the extracellular mannoprotein Cig1 is highly regulated by iron and abundant in iron-starved cells, suggesting a role in iron acquisition. Indeed, loss of Cig1 resulted in delayed growth on heme at physiological pH. Expression of CIG1 is regulated by the pH-responsive transcription factor Rim101, and loss of Rim101 also impaired growth on heme. A cig1 delta mutant was less susceptible than the wild-type strain to noniron metalloporphyrins, further indicating a role for Cig1 in heme uptake. Recombinant Cig1 exhibited the absorbance spectrum of a heme-binding protein upon heme titration, and Cig1 may therefore function as a hemophore at the cell surface. Cig1 contributed to virulence in a mouse model of cryptococcosis but only in a mutant that also lacked the high-affinity iron uptake system. Overall, Cig1-mediated heme uptake is a potential therapeutic target in C. neoformans.
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