Translational Regulation of Candida glabrata Azole Resistance - PROJECT SUMMARY/ABSTRACT
Candida glabrata is an important human fungal pathogen capable of causing both systemic and mucosal
infections in a wide variety of immunocompromised individuals, including organ transplant recipients, cancer
patients on chemotherapy and AIDS patients. C. glabrata is the second most frequently isolated Candida
species in invasive bloodstream infections, has a high crude mortality rate (~40-60%), and has been classified
as a “serious” threat to public health by the Centers for Disease Control (CDC). While resistance of C. glabrata
clinical isolates to multiple antifungals, particularly azoles, is on the rise only three major drug classes are
available for treatment. Previous studies have shown that C. glabrata antifungal resistance can be attributed to
a variety of genetic point mutations, chromosomal rearrangements as well as increased transcription of certain
drug efflux pumps. In contrast to genetic and transcriptional mechanisms, very little is known about
translational mechanisms that control antifungal resistance in C. glabrata or other human fungal pathogens.
However, we and others have shown that long 5’ UTR-mediated translational efficiency mechanisms play an
important role in controlling the expression of several key regulators of virulence-related processes in Candida
albicans and, based on RNA-seq data, many C. glabrata genes specifically involved in azole resistance also
possess long 5’ UTRs that could be involved in translational regulation. Using genome-wide ribosome profiling,
we have recently demonstrated that the C. albicans yeast-filament transition is under widespread translational
control and several genes associated with antifungal resistance also showed altered translational efficiency
during this transition. A similar ribosome profiling analysis in Saccharomyces cerevisiae, which is more closely
related to C. glabrata, also showed significant translational expression changes in response to oxidative stress.
Many C. glabrata genes important for protein synthesis are significantly down-regulated in response to azole
treatment. In addition, only a small fraction of C. glabrata genes showing altered protein expression in azole
resistant vs. susceptible isolates also showed changes at the transcript level and evidence suggests that C.
glabrata ERG11, encoding the azole target lanosterol 14-demethylase, could be under translational control.
Based on these observations, we hypothesize that translational mechanisms play an important role in
controlling azole resistance in C. glabrata. In order to test this hypothesis, we will: 1) determine the genome-
wide translational profile of C. glabrata in response to treatment with fluconazole, the most commonly used
azole drug, 2) identify and characterize translational mechanisms important for driving C. glabrata azole
resistance. Ultimately, this study will provide a better understanding of global regulatory circuits and pathways
that control C. glabrata azole resistance at the translational level. In addition, this study will identify and
characterize several key translationally regulated factors important for C. glabrata drug resistance that could
potentially serve as targets for the development of novel antifungal strategies.