Elevated catalase expression in a fungal pathogen is a double-edged sword of iron

PLoS Pathogens

Angela Lopez Garcia¹  Carol A. Munro¹  Susan Budge¹  Rodrigo Belmonte¹  Alistair J. P. Brown¹  Neil A. R. Gow¹  Carmen Herrero-de-Dios¹  Donna M. MacCallum¹  Keunsook K. Lee¹  Aljona Kolmogorova¹  Arnab Pradhan¹  Antonio Ribeiro²  Brennan D. Martin²  Raif Yuecel³  Attila Bebes³  Janet Quinn⁴ 

[1] Aberdeen Fungal Group, MRC Centre for Medical Mycology, University of Aberdeen, Institute of Medical Sciences, Aberdeen, United Kingdom;Centre for Genome-Enabled Biology and Medicine, University of Aberdeen, Aberdeen, United Kingdom;Iain Fraser Cytometry Centre, University of Aberdeen, Institute of Medical Sciences, Aberdeen, United Kingdom;Institute for Cell and Molecular Biosciences, University of Newcastle, Newcastle upon Tyne, United Kingdom

关键词: C;    ida albicans;    Catalases;    Oxidative stress;    Peroxides;    Mouse models;    Fungal pathogens;    Neutrophils;    Kidneys;   

DOI  :  10.1371/journal.ppat.1006405

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Most fungal pathogens of humans display robust protective oxidative stress responses that contribute to their pathogenicity. The induction of enzymes that detoxify reactive oxygen species (ROS) is an essential component of these responses. We showed previously that ectopic expression of the heme-containing catalase enzyme in Candida albicans enhances resistance to oxidative stress, combinatorial oxidative plus cationic stress, and phagocytic killing. Clearly ectopic catalase expression confers fitness advantages in the presence of stress, and therefore in this study we tested whether it enhances fitness in the absence of stress. We addressed this using a set of congenic barcoded C. albicans strains that include doxycycline-conditional tetON-CAT1 expressors. We show that high basal catalase levels, rather than CAT1 induction following stress imposition, reduce ROS accumulation and cell death, thereby promoting resistance to acute peroxide or combinatorial stress. This conclusion is reinforced by our analyses of phenotypically diverse clinical isolates and the impact of stochastic variation in catalase expression upon stress resistance in genetically homogeneous C. albicans populations. Accordingly, cat1Δ cells are more sensitive to neutrophil killing. However, we find that catalase inactivation does not attenuate C. albicans virulence in mouse or invertebrate models of systemic candidiasis. Furthermore, our direct comparisons of fitness in vitro using isogenic barcoded CAT1, cat1Δ and tetON-CAT1 strains show that, while ectopic catalase expression confers a fitness advantage during peroxide stress, it confers a fitness defect in the absence of stress. This fitness defect is suppressed by iron supplementation. Also high basal catalase levels induce key iron assimilatory functions (CFL5, FET3, FRP1, FTR1). We conclude that while high basal catalase levels enhance peroxide stress resistance, they place pressure on iron homeostasis through an elevated cellular demand for iron, thereby reducing the fitness of C. albicans in iron-limiting tissues within the host.

【 授权许可】

CC BY