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. 2018 Oct 24;3(5):e00506-18.
doi: 10.1128/mSphere.00506-18.

Hog1 Regulates Stress Tolerance and Virulence in the Emerging Fungal Pathogen Candida auris

Alison M Day  1 , Megan M McNiff  2 , Alessandra da Silva Dantas  3 , Neil A R Gow  3 , Janet Quinn  1
Affiliations

Hog1 Regulates Stress Tolerance and Virulence in the Emerging Fungal Pathogen Candida auris

Alison M Day et al. mSphere. .

Abstract

Candida auris has recently emerged as an important, multidrug-resistant fungal pathogen of humans. Comparative studies indicate that despite high levels of genetic divergence, C. auris is as virulent as the most pathogenic member of the genus, Candida albicans However, key virulence attributes of C. albicans, such as morphogenetic switching, are not utilized by C. auris, indicating that this emerging pathogen employs alternative strategies to infect and colonize the host. An important trait required for the pathogenicity of many fungal pathogens is the ability to adapt to host-imposed stresses encountered during infection. Here, we investigated the relative resistance of C. auris and other pathogenic Candida species to physiologically relevant stresses and explored the role of the evolutionarily conserved Hog1 stress-activated protein kinase (SAPK) in promoting stress resistance and virulence. In comparison to C. albicans, C. auris is relatively resistant to hydrogen peroxide, cationic stress, and cell-wall-damaging agents. However, in contrast to other Candida species examined, C. auris was unable to grow in an anaerobic environment and was acutely sensitive to organic oxidative-stress-inducing agents. An analysis of C. aurishog1Δ cells revealed multiple roles for this SAPK in stress resistance, cell morphology, aggregation, and virulence. These data demonstrate that C. auris has a unique stress resistance profile compared to those of other pathogenic Candida species and that the Hog1 SAPK has pleiotropic roles that promote the virulence of this emerging pathogen.IMPORTANCE The rapid global emergence and resistance of Candidaauris to current antifungal drugs highlight the importance of understanding the virulence traits exploited by this human fungal pathogen to cause disease. Here, we characterize the stress resistance profile of C. auris and the role of the Hog1 stress-activated protein kinase (SAPK) in stress resistance and virulence. Our findings that C. auris is acutely sensitive to certain stresses may facilitate control measures to prevent persistent colonization in hospital settings. Furthermore, our observation that the Hog1 SAPK promotes C. auris virulence akin to that reported for many other pathogenic fungi indicates that antifungals targeting Hog1 signaling would be broad acting and effective, even on emerging drug-resistant pathogens.

Keywords: Candida auris; pathogenesis; stress adaptation; stress kinases.

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Figures

FIG 1
FIG 1
Stress resistance comparisons. (A) C. auris has a unique stress resistance profile. Exponentially growing Candida strains were spotted in serial dilutions onto YPD agar plates containing the indicated additives and incubated for 24 or 48 h at 30°C. (B) C. auris is more resistant than C. albicans to H2O2. Exponentially growing Candida strains were treated with 25 mM H2O2, and cell survival at the indicated times was calculated as described in Materials and Methods. (C) C. auris is sensitive to combinatorial H2O2 and cationic stress. Exponentially growing strains and 10-fold dilutions thereof were spotted onto the indicated plates and incubated at 30°C for 24 h.
FIG 2
FIG 2
Sequence comparisons of fungal HOG1 orthologues. (A) Multiple-sequence alignment of the indicated Hog1 sequences using Clustal Omega and visualized using Jalview. The top graph shows the sequence conservation: columns are highlighted with the same color where there is conservation across the compared sequences. The graph at the bottom tracks the conservation with identical amino acid sequences highlighted in yellow. C. au; C. auris, C. al; C. albicans, C. d; C. dubliniensis; S. p; S. pombe, S. c; S. cerevisiae, C. g; C. glabrata. (B) Sequence alignment of the C-terminal Hog1 sequences from C. auris, S. cerevisiae, and C. glabrata. (C) Hog1 mobility. Western blot depicting the size of Hog1 orthologues from the indicated fungal species. The predicted size of each orthologue is shown (kDa).
FIG 3
FIG 3
Construction and analysis of C. auris hog1Δ cells. (A) Schematic diagram of the strategy used to delete HOG1. (B) Western blotting of potential hog1Δ strains, identified by PCR genotyping, confirmed the deletion of Hog1. Western blot analysis of lysates prepared from the indicated strains and probed with an anti-Hog1 antibody. *, nonspecific band present in all extracts.(C) Deletion of HOG1 impacts C. auris cell morphology. DIC images of exponentially growing wild-type and hog1Δ C. auris strains. (D) C. auris cells lacking HOG1 aggregate. Micrographs of wild-type and hog1Δ strains grown overnight in YPD medium. Images of culture tubes demonstrate the rapid sedimentation of cells lacking HOG1. (E) Deletion of HOG1 impacts resistance to cell-wall-damaging agents. Exponentially growing strains were spotted onto rich medium plates containing the indicated additives and incubated at 30°C for 24h. (F) C. auris hog1Δ cells exhibit more exposed chitin.
FIG 4
FIG 4
Stress-protective roles of C. auris Hog1. (A) Hog1 is required for resistance to diverse stresses. Exponentially growing cells were spotted in serial dilutions onto YPD agar plates containing the indicated additives and incubated for 24 or 48 h at 30°C. (B) Hog1 is activated in response to diverse stresses. Western blots depicting Hog1 phosphorylation in response to the indicated stresses. Blots were probed for phosphorylated Hog1 (Hog1-P), stripped, and reprobed for total Hog1 (Hog1).
FIG 5
FIG 5
C. elegans model of infection. (A) C. auris displays comparable virulence to C. albicans in C. elegans. (B) Deletion of Hog1 attenuates C. auris virulence in C. elegans. In both experiments, nematodes were infected with the indicated strains and the survival was monitored daily. These data are from a single experiment; two further independent biological replicates are shown in Fig. S4 in the supplemental material.
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