Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies

Huang, Xin; Hurabielle, Charlotte; Drummond, Rebecca A.; Bouladoux, Nicolas; Desai, Jigar V.; Sim, Choon Kiat; Belkaid, Yasmine; Lionakis, Michail S.; Segre, Julia A.

doi:10.1016/j.chom.2020.12.002

Cited by 73 publications

(93 citation statements)

References 67 publications

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“…The global prevalence of C. auris is characterized by the seemingly simultaneous emergence of four distinct genetic clades, differing on the scale of hundreds of thousands of single nucleotide polymorphisms (SNPs), with a potential fifth clade recently identified 2 , 3 . Individual isolates exhibit significant heterogeneity both within and between clades, including in murine models of infection and colonization 4 , 5 . The continually increasing understanding of biologically and clinically relevant phenotypic variation among C. auris isolates, and the variation between C. auris and other well-studied model organisms, emphasizes the need for facile genetic manipulation approaches to allow for mechanistic characterization of this organism.…”

Section: Introductionmentioning

confidence: 99%

Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains

Santana

O’Meara

2021

Nat Commun

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Candida auris is an emerging healthcare-associated pathogen of global concern. Recent reports have identified C. auris isolates that grow in cellular aggregates or filaments, often without a clear genetic explanation. To investigate the regulation of C. auris morphogenesis, we applied an Agrobacterium-mediated transformation system to all four C. auris clades. We identified aggregating mutants associated with disruption of chitin regulation, while disruption of ELM1 produced a polarized, filamentous growth morphology. We developed a transiently expressed Cas9 and sgRNA system for C. auris that significantly increased targeted transformation efficiency across the four C. auris clades. Using this system, we confirmed the roles of C. auris morphogenesis regulators. Morphogenic mutants showed dysregulated chitinase expression, attenuated virulence, and altered antifungal susceptibility. Our findings provide insights into the genetic regulation of aggregating and filamentous morphogenesis in C. auris. Furthermore, the genetic tools described here will allow for efficient manipulation of the C. auris genome.

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Section: Introductionmentioning

confidence: 99%

Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains

Santana

O’Meara

2021

Nat Commun

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“…This poor penetration is anticipated to limit its effectiveness against microorganisms deeper in the skin, including hair follicles. In another work, Huang et al found C. auris residing deep within the hair follicles of mice for months following initial colonization, consistent with an infectious reservoir [37]. Considering that chlorhexidine is expected to reach only minimal concentrations in the follicles, colonization at this site may help explain the difficulty of eliminating C. auris in healthcare settings.…”

Section: Discussionmentioning

confidence: 87%

Augmenting the Activity of Chlorhexidine for Decolonization of Candida auris from Porcine skin

Johnson

Eix

Lam

et al. 2021

JoF

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Candida auris readily colonizes skin and efficiently spreads among patients in healthcare settings worldwide. Given the capacity of this drug-resistant fungal pathogen to cause invasive disease with high mortality, hospitals frequently employ chlorhexidine bathing to reduce skin colonization. Using an ex vivo skin model, we show only a mild reduction in C. auris following chlorhexidine application. This finding helps explain why chlorhexidine bathing may have failures clinically, despite potent in vitro activity. We further show that isopropanol augments the activity of chlorhexidine against C. auris on skin. Additionally, we find both tea tree (Melaleuca alternifolia) oil and lemongrass (Cymbopogon flexuosus) oil to further enhance the activity of chlorhexidine/isopropanol for decolonization. We link this antifungal activity to individual oil components and show how some of these components act synergistically with chlorhexidine/isopropanol. Together, the studies provide strategies to improve C. auris skin decolonization through the incorporation of commonly used topical compounds.

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“…Given that SAPs are implicated in fungal adhesion and tissue invasion (Naglik et al, 2003), we speculate that SAP2 deregulation may also contribute to or is even critically determining attachment to biotic surfaces such as human skin. This can now be tested with appropriate skin models of fungal colonization (Huang et al, 2020;Rakita et al, 2020). Importantly, the pronounced adhesion to skin not only is a key trait of C. auris pathophysiology, it has been recognized as the most important route of person-toperson transmission in hospital settings, thus contributing to the global spreading and pandemic potential of C. auris (Forsberg et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the Centers of Disease Control and Prevention (CDC) has recently recognized the pandemic potential, and classified it as a global threat to human health, thus requiring urgent attention in medicare for the next decade (https://www.cdc.gov/fungal/candida-auris; (Meis and Chowdhary, 2018). Recent studies provide first glimpses about evolution, morphogenetic plasticity, host interactions and skin colonization behavior of different C. auris clades (Muñoz et al, 2018;Yue et al, 2018;Bruno et al, 2020;Chow et al, 2020;Huang et al, 2020). However, basic knowledge about C. auris cell biology or molecular mechanisms of its phenotypic diversification are lagging behind.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Signatures Predict Phenotypic Variations of Candida auris

Jenull

Tscherner

Kashko

et al. 2021

Front. Cell. Infect. Microbiol.

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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.

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Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies

Cited by 73 publications

References 67 publications

Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains

Forward and reverse genetic dissection of morphogenesis identifies filament-competent Candida auris strains

Augmenting the Activity of Chlorhexidine for Decolonization of Candida auris from Porcine skin

Transcriptome Signatures Predict Phenotypic Variations of Candida auris

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