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Front. Microbiol. | doi: 10.3389/fmicb.2019.00027

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

 Taiga Miyazaki1*,  Shintaro Shimamura2*, Masato Tashiro3,  Takahiro Takazono3,  Tomomi Saijo2, Kazuko Yamamoto2, Yoshifumi Imamura2,  Koichi Izumikawa3, Katsunori Yanagihara3, Shigeru Kohno4 and Hiroshi Mukae2
  • 1Nagasaki University Graduate School of Biomedical Sciences, Department of Infectious Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Japan
  • 2Nagasaki University Hospital, Japan
  • 3Graduate School of Biomedical Sciences, Nagasaki University, Japan
  • 4Nagasaki University, Japan

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 Cgatg1∆ 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 Cgatg1∆ 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 Cgatg1∆ 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.

Keywords: Autophagy, Atg1, Candida glabrata, Virulence, reactive oxygen species

Received: 28 Oct 2018; Accepted: 09 Jan 2019.

Edited by:

Dominique Sanglard, Université de Lausanne, Switzerland

Reviewed by:

Miguel C. Teixeira, Universidade de Lisboa, Portugal
Erika Shor, Center for Discovery and Innovation, Hackensack Meridian Health, United States  

Copyright: © 2019 Miyazaki, Shimamura, Tashiro, Takazono, Saijo, Yamamoto, Imamura, Izumikawa, Yanagihara, Kohno and Mukae. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD, PhD. Taiga Miyazaki, Department of Infectious Diseases, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, taiga-m@nagasaki-u.ac.jp
PhD. Shintaro Shimamura, Nagasaki University Hospital, Nagasaki, Nagasaki, Japan, sshimamu@nagasaki-u.ac.jp