Kamran, M. and Calcagno, A.M. and Findon, H. and Bignell, E. and Jones, M.D. and Warn, P. and Hopkins, P. and Denning, D.W. and Butler, G. and Rogers, T. and Muhlschlegel, F.A. and Haynes, K. (2004) Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence. Eukaryot Cell, 3 (2). pp. 546-552. ISSN 1535-9778.
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During an infection, the coordinated orchestration of many factors by the invading organism is required for disease to be initiated and to progress. The elucidation of the processes involved is critical to the development of a clear understanding of host-pathogen interactions. For Candida species, the inactivation of many fungal attributes has been shown to result in attenuation. Here we demonstrate that the Candida glabrata homolog of the Saccharomyces cerevisiae transcription factor gene ACE2 encodes a function that mediates virulence in a novel way. Inactivation of C. glabrata ACE2 does not result in attenuation but, conversely, in a strain that is hypervirulent in a murine model of invasive candidiasis. C. glabrata ace2 null mutants cause systemic infections characterized by fungal escape from the vasculature, tissue penetration, proliferation in vivo, and considerable overstimulation of the proinflammatory arm of the innate immune response. Compared to the case with wild-type fungi, mortality occurs much earlier in mice infected with C. glabrata ace2 cells, and furthermore, 200-fold lower doses are required to induce uniformly fatal infections. These data demonstrate that C. glabrata ACE2 encodes a function that plays a critical role in mediating the host-Candida interaction. It is the first virulence-moderating gene to be described for a Candida species.
|Additional information:||1535-9778 (Print) Journal Article Research Support, Non-U.S. Gov't|
|Uncontrolled keywords:||Alleles Animals Candida glabrata/genetics/*pathogenicity Candidiasis/*microbiology/pathology Chitinase/pharmacology DNA-Binding Proteins/genetics/metabolism Fungal Proteins/genetics/metabolism/*physiology Gene Silencing Interferon Type II/analysis/metabolism Interleukin-6/analysis/metabolism Liver/pathology Lung/pathology Mice Phenotype Saccharomyces cerevisiae Proteins/genetics/metabolism Transcription Factors/genetics/metabolism/*physiology Tumor Necrosis Factor-alpha/analysis/metabolism Virulence|
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences > Biomedical Research Group|
|Depositing User:||F.A. Muhlschlegel|
|Date Deposited:||09 Sep 2008 16:07|
|Last Modified:||14 Jan 2010 14:23|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/6193 (The current URI for this page, for reference purposes)|
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