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

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. ForCandida species, the inactivation of many fungal attributes has been shown to result in attenuation. Here we demonstrate that theCandida glabrata homolog of theSaccharomyces cerevisiae transcription factor geneACE2 encodes a function that mediates virulence in a novel way. Inactivation ofC. 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 withC. glabrata ace2 cells, and furthermore, 200-fold lower doses are required to induce uniformly fatal infections. These data demonstrate thatC. 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 aCandida species.