Inactivation of Transcription Factor Gene ACE2in the Fungal Pathogen Candida glabrataResults in Hypervirulence

ABSTRACTDuring 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 Candidaspecies, the inactivation of many fungal attributes has been shown to result in attenuation. Here we demonstrate that the Candida glabratahomolog of the Saccharomyces cerevisiaetranscription factor gene ACE2encodes a function that mediates virulence in a novel way. Inactivation of C. glabrata ACE2does not result in attenuation but, conversely, in a strain that is hypervirulent in a murine model of invasive candidiasis. C. glabrata ace2null 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 ace2cells, and furthermore, 200-fold lower doses are required to induce uniformly fatal infections. These data demonstrate that C. glabrata ACE2encodes a function that plays a critical role in mediating the host-Candidainteraction. It is the first virulence-moderating gene to be described for a Candidaspecies.