Filamentation in Candida auris , an emerging fungal pathogen of humans: passage through the mammalian body induces a heritable phenotypic switch

Abstract

Morphological plasticity has historically been an indicator of increased virulence among fungal pathogens, allowing rapid adaptation to changing environments. Candida auris has been identified as an emerging multidrug-resistant human pathogen of global importance. Since the discovery of this species, it has been thought that C. auris is incapable of filamentous growth. Here, we report the discovery of filamentation and three distinct cell types in C. auris: typical yeast, filamentation-competent (FC) yeast, and filamentous cells. These cell types form a novel phenotypic switching system that contains a heritable (typical yeast-filament) and a nonheritable (FC-filament) switch. Intriguingly, the heritable switch between the typical yeast and the FC/filamentous phenotype is triggered by passage through a mammalian body, whereas the switch between the FC and filamentous phenotype is nonheritable and temperature-dependent. Low temperatures favor the filamentous phenotype, whereas high temperatures promote the FC yeast phenotype. Systemic in vivo and in vitro investigations were used to characterize phenotype-specific variations in global gene expression, secreted aspartyl proteinase (SAP) activity, and changes in virulence, indicating potential for niche-specific adaptations. Taken together, our study not only sheds light on the pathogenesis and biology of C. auris but also provides a novel example of morphological and epigenetic switching in fungi.

Pseudohyphal growth of the emerging pathogenCandida aurisis triggered by genotoxic stress through the S phase checkpoint

“…Several conditions, which induce hyphal growth in C. albicans, such as incubation at 37 °C, and Lee's medium at pH3.5 or pH6.5, as well as media containing serum, isoamyl alcohol, or bleocin, were tested, but none of these triggered filamentous growth in the S. Asian (clade I) C. auris strain UACa11 (data not shown) (15). Likewise, growth at 25 °C did not produce filaments as described previously for a C. auris clinical isolate (21). However, using strain UACa11, we observed filamentous growth in the presence of sublethal concentrations of genotoxic drugs affecting DNA replication progression or inducing DNA damage (HU, MMS, and 5-FC) ( Fig.…”

The LUFS domain, its transcriptional regulator proteins, and drug resistance in the fungal pathogen Candida auris

“…How could a single amino acid change in this insert region affect filamentation or other processes that require the efficient functioning of the Flo8 as a transcriptional activator? If filamentation benefits the AmB‐insulted fungus by helping it to protect itself from the action of AmB, as appears to be the case for C. albicans , and if the passage‐mediated increase in filamentation or filamentation competence is also an adaptive or beneficial step for the fungus, then a Flo8 S → N mutation found precisely in an AmB‐resistant strain would suggest an increase, rather than a decrease, in filamentation or filamentation competence, and thus possibly an increase in the net efficiency of transcription events that promote such properties.…”

“…These reasons include, for example, the observation that filamentation is linked to Flo8 or FLO genes, and that a strategy involving filamentation and/or filamentation competence could be employed by C. auris for its survival/virulence within the host and/or for its resistance to antifungal drugs. Indeed, it has been observed that passage through the host organism favors a heritable switch of C. auris to a filamentous or filamentation‐competent form . Correspondingly, in the congeneric species Candida albicans , experimental results strongly suggest that filamentation protects the yeast cells against programmed cell death induced by the antifungal drug amphotericin B (AmB) .…”

“…Indeed, it has been observed that passage through the host organism favors a heritable switch of C. auris to a filamentous or filamentation-competent form. 11 Correspondingly, in the congeneric species Candida albicans, experimental results strongly suggest that filamentation protects the yeast cells against programmed cell death induced by the antifungal drug amphotericin B (AmB). 12,13 Other processes in which Flo8 and its target genes are (or might reasonably be considered to be) involved, and that are also relevant for understanding C. auris, include an aggregation that has been noted for this species, formation of biofilms in clinical settings, adhesion processes within the host, and adhesion to dry objects or survival under other adverse conditions that may partly account for its unusual resilience and transmission in or between hospitals (see 10 and references therein).…”

On the emergence ofCandida auris: climate change, azoles, swamps and birds

“…Of note, sea birds may serve as reservoirs for indirect transmission of drug resistant Candida species, such as C. glabrata , to humans (24). The uncanny ability of C auris for niche-specific adaptations, first in the environment, then in an avian host might have led as a third step to the ultimate establishment as a human pathogens through genetic and epigenetic switches (25). The hypothesis that C. auris broke the mammalian thermal barrier through adaptation to climate change suggests several experimental lines of investigation to obtain evidence for and against it.…”