Transient Mitochondria Dysfunction Confers Fungal Cross-Resistance against Phagocytic Killing and Fluconazole

• Published in: mBio 2021-06, Vol.12 (3), p.e0112821-e0112821
• Main Authors: Siscar-Lewin, Sofía, Gabaldón, Toni, Aldejohann, Alexander M, Kurzai, Oliver, Hube, Bernhard, Brunke, Sascha
• Format: Article
• Language: English
• Subjects: Antifungal Agents - pharmacology; Candida glabrata - drug effects; Candida glabrata - genetics; Candida glabrata - growth & development; Candida glabrata - pathogenicity; Candidiasis - microbiology; Drug Resistance, Fungal - genetics; Fluconazole - pharmacology; Gene Expression Regulation, Fungal; Humans; Macrophages - microbiology; Microbial Sensitivity Tests; Mitochondria - metabolism; Mitochondria - pathology; Phagocytes; Phagocytosis; Research Article; Virulence - genetics
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.01128-21

Loss or inactivation of antivirulence genes is an adaptive strategy in pathogen evolution. Candida glabrata is an important opportunistic pathogen related to baker's yeast, with the ability to both quickly increase its intrinsic high level of azole resistance and persist within phagocytes. During C. glabrata's evolution as a pathogen, the mitochondrial DNA polymerase CgMip1 has been under positive selection. We show that deletion not only triggers loss of mitochondrial function and a phenotype, but increases C. glabrata's azole and endoplasmic reticulum (ER) stress resistance and, importantly, its survival in phagocytes. The same phenotype is induced by fluconazole and by exposure to macrophages, conferring a cross-resistance between antifungals and immune cells, and can be found in clinical isolates despite a slow growth of strains. This suggests that constitutes a bet-hedging strategy of C. glabrata and, potentially, a relevant cause of azole resistance. Mitochondrial function may therefore be considered a potential antivirulence factor. Candida glabrata is an opportunistic pathogen whose incidence has been increasing in the last 40 years. It has risen to become the most prominent non-Candida albicans (NCAC) species to cause candidemia, constituting about one-third of isolates in the United States, and steadily increasing in European countries and in Australia. Despite its clinical importance, C. glabrata's pathogenicity strategies remain poorly understood. Our research shows that loss of mitochondrial function and the resulting phenotype is advantageous for C. glabrata to cope with infection-related stressors, such as antifungals and host immune defenses. The (cross-)resistance against both these factors may have major implications in the clinical outcome of infections with this major fungal pathogen.