Our group studies the yeast Candida albicans, which is a member of the microbiota of the gastrointestinal and genitourinary tracts in most healthy persons. Especially in immunocompromised patients, this normally harmless fungus can become a pathogen and cause superficial infections of the mucosa and skin as well as life-threatening systemic infections after dissemination via the bloodstream. Adaptation of the gene expression pattern to altered environmental conditions in new host niches, induction of developmental programs that involve changes in its morphology, and genomic alterations that result in the acquisition of novel phenotypic traits all contribute to the success of C. albicans as a commensal and pathogen in the human host. For example, in response to various signals C. albicans changes from the budding yeast morphology to filamentous growth forms, which facilitates tissue invasion (Fig. 1). A change from heterozygosity to homozygosity at the mating type locus enables the fungus to switch from the normal (“whiteâ€) yeast morphology to a another cell type, termed opaque. Opaque cells are less virulent than white cells, but they avoid recognition by phagocytic cells and may thus escape from certain host defense mechanisms (Fig. 2). Furthermore, opaque cells are the mating-competent form of C. albicans and allow the exchange of genetic information between strains, thus contributing to the genetic diversity and evolution of the fungus by the combination of advantageous traits. An illustrative example of genetic alterations conferring a selective advantage are mutations that result in increased resistance to antifungal drugs, which are commonly observed during antifungal therapy. Once such mutations arise, they are often followed by additional genomic changes, like aneuploidies and loss of heterozygosity, which further increase drug resistance.
Our lab is especially interested in the transcriptional regulation of virulence-associated genes, developmental programs, and antifungal drug resistance. We have elucidated the stage- and tissue-specific activation of C. albicans virulence genes in vivo during experimental infections and could define components of signaling pathways that control morphogenesis and virulence gene expression. In addition, we have identified transcription factors that regulate drug resistance genes and uncovered gain-of-function mutations in these regulators that are responsible for the increased drug resistance of clinical C. albicans isolates. By creating strains containing various resistance mutations in an isogenic background, we are currently investigating the impact of different types of mutations and combinations thereof on drug resistance as well as the consequences of the associated alterations in gene expression for the fitness of C. albicans in vitro and in vivo. With the help of these strains we also address the question of how C. albicans may overcome potential costs of specific drug resistance mechanisms, which will help us to understand the evolution of the fungus within its mammalian host.
Recently, we have generated genome-wide expression libraries of transcription factors and upstream signaling proteins, which allowed us to identify novel regulators of filamentous growth and white-opaque switching. The identification of these regulatory factors has raised intriguing hypotheses about in vivo conditions and signals that may induce different developmental fates of C. albicans cells, which we are currently testing. Furthermore, we have developed a universally applicable method to artifically activate a fungus-specific transcription factor family, the zinc cluster proteins, and thereby reveal their biological functions. We have created a comprehensive set of strains expressing hyperactive forms of these transcription factors, which resulted in the identification of previously unknown regulators of resistance to drugs and other stress conditions encountered in the host. We use transcriptional profiling and genome-wide in vivo DNA binding studies to identify the target genes of the transcription factors and understand their mechanism of action. Detailed insights into the virulence and drug resistance mechanisms of C. albicans will hopefully also reveal strategies for the development of novel antifungal drugs.