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Eukaryotic Cell, April 2004, p. 546-552, Vol. 3, No. 2
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.2.546-552.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inactivation of Transcription Factor Gene ACE2 in the Fungal Pathogen Candida glabrata Results in Hypervirulence

Mohammed Kamran ,1,{dagger},{ddagger} Ana-Maria Calcagno,1,2,{dagger} Helen Findon,1 Elaine Bignell,1 Michael D. Jones,1 Peter Warn,3 Philip Hopkins,1 David W. Denning,3 Geraldine Butler,4 Thomas Rogers,1 Fritz A. Mühlschlegel,5 and Ken Haynes1*

Department of Infectious Diseases, Imperial College London, London,1 School of Medicine, University of Manchester, Manchester,3 Research School of Biosciences, University of Kent Canterbury, United Kingdom,5 Center of Microbiology and Cell Biology, Venezuelan Institute for Scientific Research, Caracas, Venezuela,2 Department of Biochemistry, The Conway Institute, University College Dublin, Dublin, Ireland4

Received 14 November 2003/ Accepted 10 December 2003

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.

* Corresponding author. Mailing address: Department of Infectious Diseases, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom. Phone: 44 (0)20 8383 1245. Fax: 44 (0)20 8383 3394. E-mail: k.haynes{at}imperial.ac.uk.

{dagger} M.K. and A.-M.C. contributed equally to this work.

{ddagger} Present address: School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom.

Eukaryotic Cell, April 2004, p. 546-552, Vol. 3, No. 2
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.2.546-552.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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