AUTHOR=Shimamura Shintaro , Miyazaki Taiga , Tashiro Masato , Takazono Takahiro , Saijo Tomomi , Yamamoto Kazuko , Imamura Yoshifumi , Izumikawa Koichi , Yanagihara Katsunori , Kohno Shigeru , Mukae Hiroshi 

TITLE=Autophagy-Inducing Factor Atg1 Is Required for Virulence in the Pathogenic Fungus Candida glabrata

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.00027

DOI=10.3389/fmicb.2019.00027

ISSN=1664-302X

ABSTRACT=<p><italic>Candida glabrata</italic> is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. <italic>C. glabrata</italic> is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of <italic>C. glabrata</italic> 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 <italic>C. glabrata</italic> virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) in <italic>C. glabrata</italic>. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The <italic>Cgatg1</italic>Δ strain was sensitive to nitrogen starvation and H<sub>2</sub>O<sub>2</sub>, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the <italic>CgATG1</italic>-reconstituted strain <italic>in vitro</italic>. Upon infecting mouse peritoneal macrophages, the <italic>Cgatg1</italic>Δ strain showed higher mortality from phagocytosis by macrophages. Finally, <italic>in vivo</italic> experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The <italic>Cgatg1</italic>Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to <italic>C. glabrata</italic> virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in <italic>Candida</italic> species.</p>