Open AccessTwo Major Inositol Transporters and Their Role in Cryptococcal Virulence
Author(s) -
Yina Wang,
TongBao Liu,
Guillaume Delmas,
Steven Park,
David S. Perlin,
Chaoyang Xue
Publication year - 2011
Publication title -
eukaryotic cell
Language(s) - English
Resource type - Journals
eISSN - 1535-9778
pISSN - 1535-9786
DOI - 10.1128/ec.00327-10
Subject(s) - cryptococcus neoformans , virulence , biology , inositol , mutant , microbiology and biotechnology , transporter , cryptococcus , cryptococcosis , gene , genetics , receptor
Cryptococcus neoformans is an AIDS-associated human fungal pathogen and the most common cause of fungal meningitis, with a mortality rate over 40% in AIDS patients. Significant advances have been achieved in understanding its disease mechanisms. Yet the underlying mechanism of a high frequency of cryptococcal meningitis remains unclear. The existence of high inositol concentrations in brain and our earlier discovery of a large inositol transporter (ITR ) gene family inC. neoformans led us to investigate the potential role of inositol inCryptococcus -host interactions. In this study, we focus on functional analyses of two majorITR genes to understand their role in virulence ofC. neoformans . Our results show thatITR1A andITR3C are the only twoITR genes among 10 candidates that can complement the growth defect of aSaccharomyces cerevisiae strain lacking inositol transporters. BothS. cerevisiae strains heterologously expressingITR1A orITR3C showed high inositol uptake activity, an indication that they are major inositol transporters. Significantly,itr1a itr3c double mutants showed significant virulence attenuation in murine infection models. Mutating bothITR1A andITR3C in anino1 mutant background activates the expression of several remainingITR candidates and does not show more severe virulence attenuation, suggesting that both inositol uptake and biosynthetic pathways are important for inositol acquisition. Overall, our study provides evidence that host inositol and fungal inositol transporters are important forCryptococcus pathogenicity.