TheCandida aurisHog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence

Abstract

AbstractCandida auris, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemicC. aurisinfections 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 thatC. auris,unlike mostCandidaspecies, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible forC. aurisskin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report thatC. aurisHog1 mitogen-activated protein kinase (MAPK) is essential for efficient skin colonization, intradermal persistence, as well as systemic virulence. RNA-seq analysis of wildtype parental andhog1Δ mutant strains revealed marked down-regulation of genes involved in processes such as cell adhesion, cell-wall rearrangement, and pathogenesis inhog1Δ mutant compared to the wildtype parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell-wall architecture, as thehog1Δ 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 formationin vitroand fungal survival when challenged with primary murine macrophages and neutrophilsex vivo. Collectively, these findings have important implications for understanding theC. aurisskin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.ImportanceCandida aurisis a World Health Organization (WHO) fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention (CDC).C. aurishas 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 ofC. auris. Therefore, understandingC. aurisskin colonization mechanisms are critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis ofC. aurisskin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator ofC. aurisskin colonization. These findings lay foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.