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.
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| http://dx.doi.org/10.1016/j.chom.2011.02.003 | DOI Listing |
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Toward an integrated model of capsule regulation in Cryptococcus neoformans.
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Center for Genome Sciences and Systems Biology and Departments of Computer Science and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray analysis of cells stimulated to form capsule over a range of growth conditions to identify a transcriptional signature associated with capsule enlargement.
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FEMS Immunol Med Microbiol
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Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
After inhalation of infectious particles, Cryptococcus neoformans resides in the alveolar spaces, where it can survive and replicate in the extracellular environment. This yeast has developed different mechanisms to avoid internalization by phagocytic cells, the main one being a polysaccharide capsule around the cell body, which inhibits the uptake of the yeast by macrophages. In addition, capsule-independent mechanisms have also been described, such as the production of antiphagocytic proteins.
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Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16(th) Street, San Francisco, CA 94158-2200, USA. Electronic address:
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.
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Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University of Wisconsin, Madison, WI 53706, USA; Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, School of Medicine and Public Health, 1300 University of Wisconsin, Madison, WI 53706, USA. Electronic address:
While a polysaccharide capsule is known to be important for preventing phagocytosis of the human pathogen Cryptococcus neoformans, other antiphagocytic pathways have been generally elusive. Now, a capsule-independent pathway has been identified that prevents macrophages from ingesting the fungus, contributing to evasion of the host immune response.
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