title: A major role for capsule-independent phagocytosis-inhibitory mechanisms in mammalian infection by Cryptococcus neoformans.
abstract: The antiphagocytic polysaccharide capsule of the human fungal pathogen Cryptococcus neoformans is a major virulence attribute. However, previous studies of the pleiotropic virulence determinant Gat201, a GATA family transcription factor, suggested that capsule-independent antiphagocytic mechanisms exist. We have determined that Gat201 controls the mRNA levels of ∼1100 genes (16% of the genome) and binds the upstream regions of ∼130 genes. Seven Gat201-bound genes encode for putative and known transcription factors--including two previously implicated in virulence--suggesting an extensive regulatory network. Systematic analysis pinpointed two critical Gat201-bound genes, GAT204 (a transcription factor) and BLP1, which account for much of the capsule-independent antiphagocytic function of Gat201. A strong correlation was observed between the quantitative effects of single and double mutants on phagocytosis in vitro and on host colonization in vivo. This genetic dissection provides evidence that capsule-independent antiphagocytic mechanisms are pivotal for successful mammalian infection by C. neoformans.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Chun
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA.
authors.forename: Jessica C S
authors.initials: JCS
authors.lastname: Brown
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA. Electronic address: hitenmadhani@gmail.com.
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Madhani
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000502:physiology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D050980:GATA Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010587:Phagocytosis; D015533:Transcriptional Activation; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D050980:GATA Transcription Factors; D037521:Virulence Factors