Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata

Abstract

The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings.

The MAP kinase Bbslt2 controls growth, conidiation, cell wall integrity, and virulence in the insect pathogenic fungus Beauveria bassiana

“…''S'' in bracket of labels indicates that cultures were from medium supplemented with 1 M sorbitol at the indicated temperature. lead to net water gain in the mutant, consistent with previous findings with other fungi (Miyazaki et al, 2010;Yago et al, 2011).…”

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

“…In contrast, sorbitol completely suppressed the temperature sensitivity of the Cgpan1 mutant. The Cgslt2 mutant was neither temperaturesensitive for growth at 37°C nor at 42°C; this is in contrast to an earlier study reporting decreased tolerance of Cgslt2⌬ mutants to elevated temperature (46). This discrepancy could be due to differences in the genetic background of the parental strains.…”

Together we are strong—cell wall integrity sensors in yeasts

“…This will be of special interest for pathogenic fungi, such as some Candida species. Although similar signalling cascades are most likely involved in ensuring cell integrity in Candida albicans and Candida glabrata, and homologues to the S. cerevisiae CWI sensor genes can be found in the C. albicans genome, only CaWsc1 has so far been shown to increase the sensitivity towards Caspofungin [35,37]. To our knowledge, no detailed study of sensor functions has been presented for either Candida species or for the other model eukaryotic yeast, Schizosaccharomyces pombe.…”