Abstract
Health care facilities are facing serious threats by the recently emerging human fungal pathogen Candida auris owing to its pronounced antifungal multidrug resistance and poor diagnostic tools. Distinct C. auris clades evolved seemingly simultaneously at independent geographical locations and display both genetic and phenotypic diversity. Although comparative genomics and phenotypic profiling studies are increasing, we still lack mechanistic knowledge about the C. auris species diversification and clinical heterogeneity. Since gene expression variability impacts phenotypic plasticity, we aimed to characterize transcriptomic signatures of C. auris patient isolates with distinct antifungal susceptibility profiles in this study. First, we employed an antifungal susceptibility screening of clinical C. auris isolates to identify divergent intra-clade responses to antifungal treatments. Interestingly, comparative transcriptional profiling reveals large gene expression differences between clade I isolates and one clade II strain, irrespective of their antifungal susceptibilities. However, comparisons at the clade levels demonstrate that minor changes in gene expression suffice to drive divergent drug responses. Finally, we functionally validate transcriptional signatures reflecting phenotypic divergence of clinical isolates. Thus, our results suggest that large-scale transcriptional profiling allows for predicting phenotypic diversities of patient isolates, which may help choosing suitable antifungal therapies of multidrug-resistant C. auris.
Highlights
Infectious diseases pose a major threat to human health, which is further driven by the ever-ongoing emergence of new pathogens (Satoh et al, 2009; Cloeckaert and Kuchler, 2020; Wu et al, 2020)
We tested fungal susceptibilities representative from all antifungal classes and included reference control strains such as C. albicans (SC5314), C. glabrata (ATCC2001) and the initial C. auris isolate from Japan (CBS10913, clade II; (Satoh et al, 2009))
Isolates 470147 and 470154 were much less susceptible to all tested azoles, but showed reduced colony sizes upon caspofungin treatment when compared to isolate 470140 (Figure 1A). In line with this observation, clustering based on colony sizes upon antifungal treatment confirmed that isolates 470147 and 470154 clustered apart from isolate 470140 based on their susceptibility profiles (Figure 1B)
Summary
Infectious diseases pose a major threat to human health, which is further driven by the ever-ongoing emergence of new pathogens (Satoh et al, 2009; Cloeckaert and Kuchler, 2020; Wu et al, 2020). The rapid and independent emergence of C. auris in different geographical locations (Lockhart et al, 2017; Chow et al, 2020), along with its pronounced pan-antifungal traits has sparked serious concerns. Based on genomic analysis and the initial occurrence, C. auris clusters into 4 major clades, with the most recent emergence of a possible fifth clade from Iran (Chow et al, 2019). In addition to global spreading of C. auris, this pathogen constitutes an epic clinical challenge due to poor diagnostics and because of its dramatic antifungal multidrug resistance (MDR) (Chowdhary et al, 2017; Mizusawa et al, 2017; Kordalewska and Perlin, 2019)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
