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

Arnab Pradhan, Carmen Herrero De Dios, Rodrigo Belmonte, Susan Budge, Angela Lopez Garcia, Aljona Kolmogorova, Keunsook K LEE, Brennan D Martin, Antonio Ribeiro, Attila Bebes, Raif Yuecel, Neil A R Gow, Carol A Munro, Donna M MacCallum, Janet Quinn, Alistair J P Brown

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Abstract

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.

Original languageEnglish
Article number1006405
Pages (from-to)1-25
Number of pages25
JournalPLoS Pathogens
Volume13
Issue number5
DOIs
Publication statusPublished - 22 May 2017

Fingerprint

Catalase
Iron
Candida albicans
Peroxides
Virulence
Reactive Oxygen Species
Oxidative Stress
Enzyme Induction
Doxycycline
Invertebrates
Heme
Neutrophils
Homeostasis
Cell Death
Pressure
Enzymes
Population
Ectopic Gene Expression

Keywords

  • candida albicans
  • catalase
  • stress resistance
  • Iron homeostasis
  • fitness
  • host colonisation
  • virulence

Cite this

Pradhan, A., Herrero De Dios, C., Belmonte, R., Budge, S., Lopez Garcia, A., Kolmogorova, A., ... Brown, A. J. P. (2017). Elevated catalase expression in a fungal pathogen is a double-edged sword of iron. PLoS Pathogens, 13(5), 1-25. [1006405]. https://doi.org/10.1371/journal.ppat.1006405

Elevated catalase expression in a fungal pathogen is a double-edged sword of iron. / Pradhan, Arnab; Herrero De Dios, Carmen; Belmonte, Rodrigo; Budge, Susan; Lopez Garcia, Angela ; Kolmogorova, Aljona; LEE, Keunsook K; Martin, Brennan D; Ribeiro, Antonio; Bebes, Attila; Yuecel, Raif; Gow, Neil A R; Munro, Carol A; MacCallum, Donna M; Quinn, Janet; Brown, Alistair J P.

In: PLoS Pathogens, Vol. 13, No. 5, 1006405, 22.05.2017, p. 1-25.

Research output: Contribution to journalArticle

Pradhan, A, Herrero De Dios, C, Belmonte, R, Budge, S, Lopez Garcia, A, Kolmogorova, A, LEE, KK, Martin, BD, Ribeiro, A, Bebes, A, Yuecel, R, Gow, NAR, Munro, CA, MacCallum, DM, Quinn, J & Brown, AJP 2017, 'Elevated catalase expression in a fungal pathogen is a double-edged sword of iron', PLoS Pathogens, vol. 13, no. 5, 1006405, pp. 1-25. https://doi.org/10.1371/journal.ppat.1006405
Pradhan A, Herrero De Dios C, Belmonte R, Budge S, Lopez Garcia A, Kolmogorova A et al. Elevated catalase expression in a fungal pathogen is a double-edged sword of iron. PLoS Pathogens. 2017 May 22;13(5):1-25. 1006405. https://doi.org/10.1371/journal.ppat.1006405
Pradhan, Arnab ; Herrero De Dios, Carmen ; Belmonte, Rodrigo ; Budge, Susan ; Lopez Garcia, Angela ; Kolmogorova, Aljona ; LEE, Keunsook K ; Martin, Brennan D ; Ribeiro, Antonio ; Bebes, Attila ; Yuecel, Raif ; Gow, Neil A R ; Munro, Carol A ; MacCallum, Donna M ; Quinn, Janet ; Brown, Alistair J P. / Elevated catalase expression in a fungal pathogen is a double-edged sword of iron. In: PLoS Pathogens. 2017 ; Vol. 13, No. 5. pp. 1-25.
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abstract = "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.",
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AU - Herrero De Dios, Carmen

AU - Belmonte, Rodrigo

AU - Budge, Susan

AU - Lopez Garcia, Angela

AU - Kolmogorova, Aljona

AU - LEE, Keunsook K

AU - Martin, Brennan D

AU - Ribeiro, Antonio

AU - Bebes, Attila

AU - Yuecel, Raif

AU - Gow, Neil A R

AU - Munro, Carol A

AU - MacCallum, Donna M

AU - Quinn, Janet

AU - Brown, Alistair J P

N1 - We thank our colleagues in the Aberdeen Fungal Group, Lloyd Peck (British Antarctic Survey) and John Helmann (Cornell University) for insightful discussions. We thank Christophe d’Enfert and Melanie Legrand (Institut Pasteur) for help with the design of barcodes and provision of the CIp10-PTET-GTw overexpression vector and CEC2908 strain. We are grateful to the following Core Facilities at the University of Aberdeen for their excellent technical assistance, advice and support: the Medical Research Facility; the Centre for Genome Enabled Biology and Medicine; the Iain Fraser Cytometry Centre; the Microscopy and Histology Facility; Aberdeen Proteomics; and the qPCR Facility.

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N2 - 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.

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KW - fitness

KW - host colonisation

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