Identification of Candida albicans regulatory genes governing mucosal infection.

The fungus Candida albicans thrives on a variety of human mucosae, yet the fungal determinants that contribute to fitness on these surfaces remain underexplored. Here, by screening a collection of C. albicans deletion strains in a mouse model of oral infection (oropharyngeal candidiasis), we identify several novel regulatory genes that modulate the fitness of the fungus in this locale. We investigate in detail the interplay between the host mucosa and one of the identified mutants and establish that the C. albicans transcription regulator CUP9 is a key determinant of mucosal colonisation. Deletion of cup9 resulted in the formation of more foci of colonisation and heightened persistence in infected tongues. Furthermore, the cup9 mutant produced longer and denser filaments in the oral mucosa without eliciting an enhanced local immune response. Consistent with its role in oral colonisation, we show that CUP9's top target of regulation is a major effector of Candida's adherence to buccal cells. Finally, we establish that CUP9 also governs the interplay of the fungus with vaginal epithelial cells and has a role in vaginal infections, another common mucosal disease associated with Candida. Thus, our findings reveal a mechanism whereby C. albicans can regulate proliferation on mucosal surfaces.

A Fungal Transcription Regulator of Vacuolar Function Modulates Candida albicans Interactions with Host Epithelial Cells.

Microorganisms typically maintain cellular homeostasis despite facing large fluctuations in their surroundings. Microbes that reside on human mucosal surfaces may experience significant variations in nutrient and ion availability as well as pH. Whether the mechanisms employed by these microbial cells to sustain homeostasis directly impact on the interplay with the host's mucosae remains unclear. Here, we report that the previously uncharacterized transcription regulator ZCF8 in the human-associated yeast Candida albicans maintains vacuole homeostasis when the fungus faces fluctuations in nitrogen. Genome-wide identification of genes directly regulated by Zcf8p followed by fluorescence microscopy to define their subcellular localization uncovered the fungal vacuole as a top target of Zcf8p regulation. Deletion and overexpression of ZCF8 resulted in alterations in vacuolar morphology and luminal pH and rendered the fungus resistant or susceptible to nigericin and brefeldin A, two drugs that impair vacuole and associated functions. Furthermore, we establish that the regulator modulates C. albicans attachment to epithelial cells in a manner that depends on the status of the fungal vacuole. Our findings, therefore, suggest that fungal vacuole physiology regulation is intrinsically linked to, and shapes to a significant extent, the physical interactions that Candida cells establish with mammalian mucosal surfaces. IMPORTANCE Candida albicans is a fungus that resides on various human mucosal surfaces. Individuals with debilitated immune systems are prone to develop C. albicans infections, which can range in severity from mucosal disease (e.g., oral thrush in AIDS patients) to life-threatening conditions (e.g., deep-seated, disseminated infections in patients undergoing organ transplants). Understanding the cellular and molecular mechanisms that this eukaryotic microbe employs to colonize different parts of the human body and to cause disease will lay the foundation for the development of novel strategies for preventing and treating C. albicans infections. This report establishes the fungal vacuole, a key organelle to the overall fungal physiology, as a key determinant of the interplay between C. albicans and mammalian mucosal surfaces.