Affiliation:
1. Department of Laboratory Medicine and Pathology, Institute of Microbiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
2. Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
Abstract
ABSTRACT
Candida auris
is an emerging yeast pathogen of major concern because of its ability to cause hospital outbreaks of invasive candidiasis and to develop resistance to antifungal drugs. A majority of
C. auris
isolates are resistant to fluconazole, an azole drug used for the treatment of invasive candidiasis. Mechanisms of azole resistance are multiple, including mutations in the target gene
ERG11
and activation of the transcription factors Tac1b and Mrr1, which control the drug transporters Cdr1 and Mdr1, respectively. We investigated the role of the transcription factor Upc2, which is known to regulate the ergosterol biosynthesis pathway and azole resistance in other
Candida
spp. Genetic deletion and hyperactivation of Upc2 by epitope tagging in
C. auris
resulted in drastic increases and decreases in susceptibility to azoles, respectively. This effect was conserved in strains with genetic hyperactivation of Tac1b or Mrr1. Reverse transcription PCR analyses showed that Upc2 regulates
ERG11
expression and also activates the Mrr1/Mdr1 pathway. We showed that upregulation of
MDR1
by Upc2 could occur independently from Mrr1. The impact of
UPC2
deletion on
MDR1
expression and azole susceptibility in a hyperactive Mrr1 background was stronger than that of
MRR1
deletion in a hyperactive Upc2 background. While Upc2 hyperactivation resulted in a significant increase in the expression of
TAC1b
,
CDR1
expression remained unchanged. Taken together, our results showed that Upc2 is crucial for azole resistance in
C. auris
, via regulation of the ergosterol biosynthesis pathway and activation of the Mrr1/Mdr1 pathway. Notably, Upc2 is a very potent and direct activator of Mdr1.
IMPORTANCE
Candida auris
is a yeast of major medical importance causing nosocomial outbreaks of invasive candidiasis. Its ability to develop resistance to antifungal drugs, in particular to azoles (e.g., fluconazole), is concerning. Understanding the mechanisms of azole resistance in
C. auris
is important and may help in identifying novel antifungal targets. This study shows the key role of the transcription factor Upc2 in azole resistance of
C. auris
and shows that this effect is mediated via different pathways, including the regulation of ergosterol biosynthesis and also the direct upregulation of the drug transporter Mdr1.
Funder
Swiss National Science Foundation
Fondation Santos-Suarez pour la Recherche Médicale
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Cell Biology,Microbiology (medical),Genetics,General Immunology and Microbiology,Ecology,Physiology