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

ABSTRACT: Candida auris is an emerging multi-drug-resistant human fungal pathogen. C. auris skin colonization results in environmental shedding, which underlies hospital transmissions, and predisposes patients to subsequent infections. We developed a murine skin topical exposure model for C. auris to dissect risk factors for colonization and to test interventions that might protect patients. We demonstrate that C. auris establishes long-term residence within the skin tissue compartment, which would elude clinical surveillance. The four clades of C. auris, with geographically distinct origins, differ in their abilities to colonize murine skin, mirroring epidemiologic findings. The IL-17 receptor signaling and specific arms of immunity protect mice from long-term C. auris skin colonization. We further determine that commonly used chlorhexidine antiseptic serves as a protective and decolonizing agent against C. auris. This translational model facilitates an integrated approach to develop strategies to combat the unfolding global outbreaks of C. auris and other skin-associated microbial pathogens.

SUBMITTER: Huang X

PROVIDER: S-EPMC7878403 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Huang Xin X Hurabielle Charlotte C Drummond Rebecca A RA Bouladoux Nicolas N Desai Jigar V JV Sim Choon K CK Belkaid Yasmine Y Lionakis Michail S MS Segre Julia A JA

Cell host & microbe 20201231 2

Candida auris is an emerging multi-drug-resistant human fungal pathogen. C. auris skin colonization results in environmental shedding, which underlies hospital transmissions, and predisposes patients to subsequent infections. We developed a murine skin topical exposure model for C. auris to dissect risk factors for colonization and to test interventions that might protect patients. We demonstrate that C. auris establishes long-term residence within the skin tissue compartment, which would elude ...[more]

PMID: 33385336

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Project description:Candida auris, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30%-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and hog1Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in hog1Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the hog1Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo. Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.ImportanceCandida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris. Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

Project description:Candida auris is an emerging fungal pathogen capable of causing invasive infections in humans. Since its first appearance around 1996, it has been isolated in countries spanning five continents. C. auris is a yeast that has the potential to cause outbreaks in hospitals, can survive in adverse conditions, including dry surfaces and high temperatures, and has been frequently misidentified by traditional methods. Furthermore, strains have been identified that are resistant to two and even all three of the main classes of antifungals currently in use. Several nuclear genome assemblies of C. auris have been published representing different clades and continents, yet until recently, the mitochondrial genomes (mtDNA chromosomes) of this species and the closely related species of C. haemulonii, C. duobushaemulonii, and C. pseudohaemulonii had not been analyzed in depth. We used reads from PacBio and Illumina sequencing to obtain a de novo reference assembly of the mitochondrial genome of the C. auris clade I isolate B8441 from Pakistan. This assembly has a total size of 28.2 kb and contains 13 core protein-coding genes, 25 tRNAs and the 12S and 16S ribosomal subunits. We then performed a comparative analysis by aligning Illumina reads of 129 other isolates from South Asia, Japan, South Africa, and South America with the B8441 reference. The clades of the phylogenetic tree we obtained from the aligned mtDNA sequences were consistent with those derived from the nuclear genome. The mitochondrial genome revealed a generally low genetic variation within clades, although the South Asian clade displayed two sub-branches including strains from both Pakistan and India. In particular, the 86 isolates from Colombia and Venezuela had mtDNA sequences that were all identical at the base level, i.e., a single conserved haplotype or mitochondrial background that exhibited characteristic differences from the Pakistan reference isolate B8441, such as a unique 25-nt insert that may affect function.

Dataset Information

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

Publications

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

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