S4.3b Candida glabrata-host interactions

Abstract

S4.3 Emergent species of the Candida genus, September 22, 2022, 10:30 AM - 12:00 PM Candida glabrata is among the most common pathogenic yeasts of humans. Yet, this fungus is phylogenetically, genetically, and phenotypically very different from other clinically relevant Candida species. This includes an unusual high level of intrinsic resistance to antifungals such as azoles. Furthermore, in contrast to the rather aggressive pathogenicity mechanisms of the dominant Candida species, C. albicans, C. glabrata seems to have evolved strategies that are based on stealth, evasion and persistence, without causing severe host cell damage during infection. For example, C. glabrata is unable to invade epithelial cells in vitro and causes only low levels of damage in standard in vitro infection models. However, the addition of a single common host protein, albumin, strongly enhances the damage potential to vaginal epithelial cells. Similar to other Candida species, the potential of C. glabrata to survive in human blood is low. However, C. glabrata can survive within macrophages for long periods without causing host cell damage and responses. This intracellular stage requires the acquisition of nutrients, such as biotin, facilitated by defined biotin up-take systems. Survival in macrophages is further supported by transient mitochondria dysfunction: C. glabrata is able to switch into a petite phenotype upon interaction with human phagocytes. The petite phenotype significantly differs from non-petite cells in its growth behavior, its interactions with the immune system, and even its resistance to antifungal drugs. Effectively, the interaction with phagocytes can render C. glabrata mostly resistant to commonly used azole drugs, and vice versa (‘cross resistance’), providing a principle mechanism by which intrinsic antifungal resistance may have evolved.SourcesSeider et al. (2011) The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol. 187(6):3072-86.Brunke and Hube. (2013) Two unlike cousins: Candida albicans and C. glabrata infection strategies. Cell Microbiol. 15(5):701-8.Kämmer et al. (2020) Survival strategies of pathogenic Candida species in human blood show independent and specific adaptations. mBio 11(5):e02435-20.Sprenger et al. (2020) Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence. Cell Microbiol. 22(7):e13197.Pekmezovic et al. (2021) Candida pathogens induce protective mitochondria-associated type I interferon signalling and a damage-driven response in vaginal epithelial cells. Nat Microbiol. 6(5):643-657.Pekmezovic et al. (2021) Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells. PLoS Pathog. 17(10):e1010037.Siscar-Lewin et al. (2021) Transient mitochondria dysfunction confers fungal cross-resistance against phagocytic killing and fluconazole. mBio 12(3):e0112821.