Roles of Elm1 in antifungal susceptibility and virulence in Candida glabrata

Sci Rep. 2020 Jun 17;10(1):9789. doi: 10.1038/s41598-020-66620-7.

Abstract

Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology
  • Candida glabrata / drug effects
  • Candida glabrata / enzymology*
  • Candida glabrata / pathogenicity
  • Candida glabrata / ultrastructure
  • Candidiasis / microbiology
  • Cell Adhesion
  • Cell Line
  • Cell Proliferation
  • Cell Wall / genetics
  • Cell Wall / physiology
  • Fungal Proteins / genetics
  • Fungal Proteins / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal
  • Mice
  • Microbial Sensitivity Tests
  • Mutagenesis
  • Phenotype
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • RNA-Seq
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Stress, Physiological
  • Virulence

Substances

  • Antifungal Agents
  • Fungal Proteins
  • Saccharomyces cerevisiae Proteins
  • Protein Kinases
  • ELM1 protein, S cerevisiae