Abstract
Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a ‘self-eating’ process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species.
Highlights
Autophagy is an evolutionarily conserved biological process in eukaryotes that involves the degradation of cytosolic molecules for recycling intracellular materials (Klionsky et al, 2016)
In S. cerevisiae, green fluorescent protein (GFP)-Atg8 is known to be cleaved by autophagy, resulting in the release of GFP, which can be detected as a marker of autophagy (Shintani and Klionsky, 2004)
GFP bands gradually became more intense as a result of nitrogen starvation and hydrogen peroxide (H2O2) exposure in the wild-type strain, whereas no GFP bands were observed over the time-course in the Cgatg1 strain (Figure 2B), indicating that autophagy was induced in response to nitrogen starvation and H2O2 exposure in a Candida glabrata Atg1 (CgAtg1)-dependent manner in C. glabrata
Summary
Autophagy is an evolutionarily conserved biological process in eukaryotes that involves the degradation of cytosolic molecules for recycling intracellular materials (Klionsky et al, 2016). Autophagy has several functions: supplying nutrients under starvation conditions, maintaining homeostasis and protein levels, clearing damaged and/or non-functional proteins, and preventing bacterial and viral infections. These functions contribute to cell longevity, development, and differentiation as well as tumor suppression (Jin et al, 2017; Chen et al, 2018; Hansen et al, 2018). In the induction of autophagy, autophagosomes, which are double-membrane cytosolic vesicles, are formed to incorporate target proteins. Fungal pathogens use autophagy to survive in a host environment with unstable nutrient supply (Khan et al, 2012). Immune defenses such as macrophages generate ROS to kill infecting pathogens (Gonzalez-Parraga et al, 2003; Thorpe et al, 2004), but it has remained obscure whether fungal autophagy affects this oxidative stress response
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