title: The iron- and cAMP-regulated gene SIT1 influences ferrioxamine B utilization, melanization and cell wall structure in Cryptococcus neoformans.
abstract: The mechanisms by which pathogens sense and transport iron are important during infection, because of the low availability of free iron in the mammalian host. Iron is a key nutritional cue for the pathogen Cryptococcus neoformans, because it influences expression of the polysaccharide capsule that is the major virulence factor of the fungus. In this study, C. neoformans mutants were constructed with a defect in the iron-regulated gene SIT1 that encodes a putative siderophore iron transporter. Analysis of mutants in serotype A and D strains demonstrated that SIT1 is required for the use of siderophore-bound iron, and for growth in a low-iron environment. The sit1 mutants also showed changes in melanin formation and cell wall density, and it was found that mutants defective in protein kinase A, which is known to influence melanization and capsule formation, showed elevated SIT1 transcripts in both the serotype A and the serotype D backgrounds. Finally, the mutants were tested for virulence in a murine model of cryptococcosis, and it was found that SIT1 was not required for virulence. Overall, these studies establish links between iron acquisition, melanin formation and cAMP signalling in C. neoformans.
authors.affiliation: Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, University of British Columbia, Vancouver BC V6T 1Z4, Canada.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Tangen
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Jung
authors.forename: Anita P
authors.initials: AP
authors.lastname: Sham
authors.forename: Tianshun
authors.initials: T
authors.lastname: Lian
authors.forename: James W
authors.initials: JW
authors.lastname: Kronstad
mesh_terms: D000818:Animals; D002473:Cell Wall / Q000378:metabolism* / Q000648:ultrastructure; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D000242:Cyclic AMP; D003676:Deferoxamine / Q000378:metabolism*; D005290:Ferric Compounds / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D007501:Iron; D008543:Melanins / Q000096:biosynthesis*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D046529:Microscopy, Electron, Transmission; D014774:Virulence
chemical_list: D005290:Ferric Compounds; D005656:Fungal Proteins; D008543:Melanins; D026901:Membrane Transport Proteins; C002577:ferrioxamine B; D000242:Cyclic AMP; D007501:Iron; D003676:Deferoxamine