Mechanisms Underlying the Exquisite Sensitivity of Candida albicans to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes

Authors

Despoina Kaloriti, University of Aberdeen
Mette Jacobsen, University of Aberdeen
Zhikang Yin, University of Aberdeen
Miranda Patterson, Newcastle University
Anna Tillmann, University of Aberdeen
Deborah A. Smith, Newcastle University
Emily Cook, University of Exeter
Tao You, University of Aberdeen
Melissa J. Grimm, Roswell Park Cancer Institute
Iryna Bohovych, University of Nebraska- LincolnFollow
Celso Grebogi, University of Aberdeen
Brahm H. Segal, Roswell Park Cancer Institute
Neil A.R. Gow, University of Aberdeen
Ken Haynes, University of Exeter
Janet Quinn, Newcastle University
Alistair J.P. Brown, University of AberdeenFollow

Date of this Version

2014

Citation

Kaloriti D, Jacobsen M, Yin Z, Patterson M, Tillmann A, Smith DA, Cook E, You T, Grimm MJ, Bohovych I, Grebogi C, Segal BH, Gow NAR, Haynes K, Quinn J, Brown AJP. 2014. Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes. mBio 5(4):e01334-14.

Comments

© 2014 Kaloriti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license.

Abstract

Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus

Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity

of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual

stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro.We also show that the high

fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as

their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic

basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference—

lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular

accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to

oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic

stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be

suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing

of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal

mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy.