A Candida auris-Specific Adhesin, Scf1, Governs Surface Association, Colonization, and Virulence
Santana, Darian
2024
Abstract
Since its initial report in 2009, the emerging fungal pathogen Candida auris has become an increasingly common source of life-threatening infection, with cases and outbreaks reported in dozens of countries on every major continent. The global prevalence of C. auris is characterized by the simultaneous emergence of six distinct clades, separated geographically and genetically on the scale of hundreds of thousands of single nucleotide polymorphisms. C. auris is recognized as an urgent and critical public health threat due to its propensity for multidrug resistance and its ability to cause healthcare associated outbreaks, although molecular understanding of the phenotypes underpinning critical clinical behaviors in C. auris remains severely limited. Early functional genetic work in C. auris was constrained by poor genetic tractability. Tools and techniques used for manipulating the genomes of other fungal species proved to be unreliable and variably effective in C. auris, contributing to the field’s limited advances in molecular insights. To address these limitations, I developed forward and reverse genetic tools optimized for C. auris and demonstrated their efficiency in promoting genetic tractability in diverse clinical isolates sourced from around the globe. These techniques demonstrated quantifiable improvements in the genetic tractability of diverse C. auris isolates over existing methods. I used these tools to identify chitin regulatory pathways as the genetic basis for an enigmatic multicellular phenotype reported in C. auris and investigated the implications of this phenotype for virulence and antifungal resistance, demonstrating their utility for characterizing genetic function in C. auris. I next investigated the peculiar ability of C. auris to spread between individuals and drive outbreaks, especially in healthcare environments. C. auris is frequently reported in association with nosocomial outbreaks, a characteristic rarely described in other Candida species. C. auris outbreaks are characterized by persistent colonization of patient skin and abiotic surfaces, which can remain positive for extensive lengths of time and serve as a source of horizontal transmission or potentiate invasive infection. Here, I investigated the molecular mechanisms of C. auris surface association to understand its colonization and transmission potential. I employed a forward genetic screen to identify SCF1 (Surface Colonization Factor), a cell surface adhesin gene that is necessary and sufficient for C. auris surface colonization. SCF1 is encoded by all C. auris clades, but appears to be lineage-specific, as homologs exist only in the haemulonii complex members C. auris and the closely related Candida haemulonii. Despite its conservation within C. auris, utilization of SCF1 and adhesive capacity varies widely among isolates. Among diverse clinical isolates representing the major genetic clades and sourced from cases and outbreaks around the world, SCF1 transcriptional control is tightly correlated with surface association. This pattern holds both between and within genetic clades, suggesting adaptation around SCF1 transcriptional control is more recent than the separation of clades. In contrast to established molecular mechanisms in conserved yeast adhesins, which rely on hydrophobic interactions to drive surface association, Scf1 relies on exposed cationic residues for electrostatic association with diverse substrates in a manner reminiscent of bivalve adhesion proteins. SCF1 is critical for C. auris biofilm formation, colonization of central venous catheters in vivo, skin colonization, and hematogenous infection, and its differential utilization is explanatory for strain-specific variation in these clinically relevant phenotypes. Together, these findings detail the discovery and characterization of critical virulence and colonization factors in C. auris.Deep Blue DOI
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Emerging fungal pathogen colonization potential
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