title: Two major inositol transporters and their role in cryptococcal virulence.
abstract: 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 in C. neoformans led us to investigate the potential role of inositol in Cryptococcus-host interactions. In this study, we focus on functional analyses of two major ITR genes to understand their role in virulence of C. neoformans. Our results show that ITR1A and ITR3C are the only two ITR genes among 10 candidates that can complement the growth defect of a Saccharomyces cerevisiae strain lacking inositol transporters. Both S. cerevisiae strains heterologously expressing ITR1A or ITR3C 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 both ITR1A and ITR3C in an ino1 mutant background activates the expression of several remaining ITR 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 for Cryptococcus pathogenicity.
authors.affiliation: Public Health Research Institute, University of Medicine and Dentistry of New Jersey, ICPH Building, Room W250H, 225 Warren Street, Newark, NJ 07103, USA.
authors.forename: Yina
authors.initials: Y
authors.lastname: Wang
authors.forename: Tong-bao
authors.initials: TB
authors.lastname: Liu
authors.forename: Guillaume
authors.initials: G
authors.lastname: Delmas
authors.forename: Steven
authors.initials: S
authors.lastname: Park
authors.forename: David
authors.initials: D
authors.lastname: Perlin
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Xue
mesh_terms: D000818:Animals; D003455:Cryptococcus neoformans / Q000472:pathogenicity*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D007294:Inositol