title: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University School of Medicine, Nagasaki, Japan. taiga-m@nagasaki-u.ac.jp
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inamine
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamauchi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nagayoshi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Saijo
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Seki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000825:Animal Structures / Q000382:microbiology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D041221:Candida glabrata / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology* / Q000528:radiation effects; D002177:Candidiasis / Q000382:microbiology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D054714:Echinocandins / Q000494:pharmacology; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006358:Hot Temperature; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D037521:Virulence Factors; C011952:nikkomycin; D020928:Mitogen-Activated Protein Kinases