Transient mitochondria dysfunction confers fungal cross-resistance between macrophages and fluconazole

Abstract

Loss or inactivation of antivirulence genes is an adaptive strategy in pathogen evolution. Candida glabrata is an important opportunistic pathogen related to bakers yeast, with the ability to both, quickly increase its intrinsic high level of azole resistance and persist within phagocytes. During C. glabratas evolution as a pathogen, the mitochondrial DNA polymerase, CgMip1, has been under positive selection. We show that CgMIP1 deletion not only triggers loss of mitochondrial function and a petite phenotype, but increases C. glabratas azole and 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 its slow growth. This suggests that petite 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.