Phenotypic Plasticity Regulates Candida albicans Interactions and Virulence in the Vertebrate Host

Abstract

Phenotypic diversity is critical to the lifestyles of many microbial species, enabling rapid responses to changes in environmental conditions. In the human fungal pathogen Candida albicans, cells exhibit heritable switching between two phenotypic states, white and opaque, which yield differences in mating, filamentous growth, and interactions with immune cells in vitro. Here, we address the in vivo virulence properties of the two cell states in a zebrafish model of infection. Multiple attributes were compared including the stability of phenotypic states, filamentation, virulence, dissemination, and phagocytosis by immune cells, and phenotypes equated across three different host temperatures. Importantly, we found that both white and opaque cells could establish a lethal systemic infection. The relative virulence of the two cell types was temperature dependent; virulence was similar at 25°C, but at higher temperatures (30 and 33°C) white cells were significantly more virulent than opaque cells. Despite the difference in virulence, fungal burden, and dissemination were similar between cells in the two states. Additionally, both white and opaque cells exhibited robust filamentation during infection and blocking filamentation resulted in decreased virulence, establishing that this program is critical for pathogenesis in both cell states. Interactions between C. albicans cells and immune cells differed between white and opaque states. Macrophages and neutrophils preferentially phagocytosed white cells over opaque cells in vitro, and neutrophils showed preferential phagocytosis of white cells in vivo. Together, these studies distinguish the properties of white and opaque cells in a vertebrate host, and establish that the two cell types demonstrate both important similarities and key differences during infection.

Alternative oxidase induction protects Candida albicans from respiratory stress and promotes hyphal growth

“…This could be due to a slower emergence of hyphae at the incubation temperature of 28 °C. A correlation between filamentation and increased virulence in this model has been noted previously (Mallick et al, 2016).…”

The planarian Schmidtea mediterranea is a new model to study host-pathogen interactions during fungal infections

“…The study of vertebrate and invertebrate in vivo models of candidiasis to date has provided important insights into the pathogenesis of fungal infections (Bergeron et al, 2017;Chamilos et al, 2007;Fuchs et al, 2010;Glittenberg et al, 2011;Gratacap et al, 2017;Mallick et al, 2016;Mylonakis, 2008;Mylonakis et al, 2007;Peterson and Pukkila-Worley, 2018;Pukkila-Worley et al, 2009a;Segal and Frenkel, 2018). However, there are still existing limitations in analyzing hostpathogen interactions in the context of the adult body and the stem cell response.…”

Phenotypic Profiling Reveals that Candida albicans Opaque Cells Represent a Metabolically Specialized Cell State Compared to Default White Cells

“…White and opaque cells exhibit a number of contrasting properties, including differences in mating competency, phagocytosis by host cells, virulence, and niche specificity (22–27). Switching between white and opaque states is usually seen in MTL homozygous strains and occurs stochastically at low frequency under standard laboratory conditions (26).…”