The emergence of Candida glabrata as a major commensal in the oral cavity of the elderly, and as the second most common yeast blood stream infection is a matter of dire concern. Because Candida glabrata is naturally drug-resistant, it puts at risk the elderly and immunocompromised, and causes chronic infections that an difficult to treat. The success of this pathogen, however, was puzzling since, unlike Candida albicans, it appeared to undergo neither high frequency phenotypic switching nor dimorphism, two developmental programs that provide mechanism for rapid adaptation in pathogenesis. We, therefore, searched for and discovered both developmental programs in C. glabrata. C. glabrata switches spontaneously, reversibly and at high frequency between four """"""""core"""""""" phenotypes distinguishable on CuSO4-containing agar, white (Wh), light brown (LB), dark brown (DB) and very dark brown (vDB), and in addition switch to and from two """"""""associated"""""""" switch phenotypes, unstable white (unWh) and irregular wrinkle (IWr). Core switching is unique in that all tested phenotypic characteristics and the expression of switching-regulated genes are graded in the hierarchies Wh less than LB less than DB less than vDB or Wh greater than LB greater than DB greater than vDB. Based upon the discovery of this uniquely graded switching system, and the recent suggestion of anatomical specialization of core switch phenotypes in the oral cavity and vagina of a chronic vaginitis patient, the following specific aims are proposed: 1) complete the characterization of switching and define the relationship of the associated switch phenotypes and the core switching system; 2) identify and characterize additional switching-regulated genes by differential hybridization screens and the use of S. cerevisiae cDNA-based arrays; 3) using REMI mutagenesis, identify and characterize genes involved in the switching process; 4) functionally characterize the cis-acting sequences and trans-acting factors involved in the graded expression; 5) discriminate between genes involved in the unWh and IWr phenotypes and genes involved in the pseudohypha and bud growth forms and 6) test whether switching affects drug susceptibility, other virulence traits and virulence in animal models, and confirm that the core switch phenotypes exhibit anatomical specialization.
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