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Regulation of Candida albicans gastrointestinal colonization

  • Author(s): Witchley, Jessica
  • Advisor(s): Noble, Suzanne M
  • et al.
Abstract

Candida albicans is both a fungal commensal as well as an opportunistic pathogen of humans. This fungus does not have a known environmental niche and exists primarily as a commensal of the human skin, gastrointestinal tract and genitourinary tract. It has been established that the same strains that are found in commensal niches are the ones that cause diseases. This suggests a model of infection whereby the commensal strains are triggered to become pathogenic by the host environment. C. albicans can adopt many different cell morphologies and each is accompanied by a distinct expression profile. Through a series of genetic screens and candidate based approaches, I explore the role for regulators of fungal morphology in the commensal fitness of C. albicans in the gastrointestinal tract. First, I developed a method for screening large numbers of C. albicans mutants in a single infection that led to the role of transcription factors that are activators of the yeast-to-hyphal transition as inhibitors of commensal fitness. RNA expression profiling of a mutant of one of these hypha-activating transcription factors, Ume6, led to the establishment of a role for a secreted effector, Sap6, in modulating the commensal fitness of C. albicans, likely through a host-mediated response to the fungus. Next, I established a role for regulators of the white-opaque switch in commensal fitness. Interestingly, the direction of commensal regulation did not always line up with the predicted role for these transcription factors based on their role in regulation of the white-to-opaque switch. To explore how these transcription factors control the commensal program, I developed a method, Calling Card-seq, for determining in vivo binding events of these regulators in the mammalian GI tract. Together with mRNA-seq, this technique shows promise for defining the regulatory targets of transcription factors in vivo that modulate the commensal and virulent properties of this important human pathogen.

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