Hypoxia promotes immune evasion by triggering β-glucan masking on the Candida albicans cell surface via mitochondrial and cAMP-protein kinase A signalling

Arnab Pradhan, Gabriela Avelar, Judith M. Bain, Delma Childers, Daniel E. Larcombe, Mihai G. Netea, Elena Shekhova, Carol A. Munro, Gordon D. Brown, Lars Erwig, Neil A. R. Gow, Alistair J. P. Brown

Research output: Contribution to journalArticle

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Abstract

Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen whilst minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonise hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans, Candida albicans, includes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow derived macrophages and decreased production of IL-10, RANTES and TNFα by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect upon C. albicans host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signalling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ and upc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed by goa1Δ and upc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δ tpk2Δ) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing β-glucan masking via a mitochondrial-cAMP-PKA signalling pathway, thereby modulating local immune responses and promoting fungal colonisation.
Original languageEnglish
Article numbere01318-18
JournalmBio
Volume9
Early online date6 Nov 2018
DOIs
Publication statusE-pub ahead of print - 6 Nov 2018

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Immune Evasion
Glucans
Mitochondrial Proteins
Cyclic AMP-Dependent Protein Kinases
Candida albicans
Oxygen
Mutation
Cell Hypoxia
Chemokine CCL5
Hypoxia
Phagocytosis
Interleukin-10
Cell Wall
Hydrogen Peroxide
Reactive Oxygen Species
Blood Cells
Macrophages
Phenotype
Membranes

Keywords

  • hypoxia
  • candida albicans
  • cell-wall
  • β-glucan masking
  • mitochondrial signalling
  • cAMP-protein kinase A signalling

Cite this

Hypoxia promotes immune evasion by triggering β-glucan masking on the Candida albicans cell surface via mitochondrial and cAMP-protein kinase A signalling. / Pradhan, Arnab; Avelar, Gabriela; Bain, Judith M.; Childers, Delma; Larcombe, Daniel E.; Netea, Mihai G.; Shekhova, Elena; Munro, Carol A.; Brown, Gordon D.; Erwig, Lars; Gow, Neil A. R.; Brown, Alistair J. P.

In: mBio, Vol. 9, e01318-18, 06.11.2018.

Research output: Contribution to journalArticle

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title = "Hypoxia promotes immune evasion by triggering β-glucan masking on the Candida albicans cell surface via mitochondrial and cAMP-protein kinase A signalling",
abstract = "Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen whilst minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonise hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans, Candida albicans, includes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow derived macrophages and decreased production of IL-10, RANTES and TNFα by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect upon C. albicans host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signalling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ and upc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed by goa1Δ and upc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δ tpk2Δ) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing β-glucan masking via a mitochondrial-cAMP-PKA signalling pathway, thereby modulating local immune responses and promoting fungal colonisation.",
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author = "Arnab Pradhan and Gabriela Avelar and Bain, {Judith M.} and Delma Childers and Larcombe, {Daniel E.} and Netea, {Mihai G.} and Elena Shekhova and Munro, {Carol A.} and Brown, {Gordon D.} and Lars Erwig and Gow, {Neil A. R.} and Brown, {Alistair J. P.}",
note = "We are very grateful to the members of our Iain Fraser Cytometry Centre and Microscopy and Histology Core Facility for their superb help, advice and support. We also thank our generous colleagues in the Candida community, and in particular Ana Traven, Jan Quinn, Guanghua Huang, Suzanne Noble, Donna MacCallum, Liz Johnson, Karl Kuchler, Patrick van Dijck, Rich Calderone and Malcolm Whiteway for providing strains used in this study. This work was funded by grants from the UK Medical Research Council [www.mrc.ac.uk], to AJPB, NARG, LPE, MN (MR/M026663/1), and by PhD studentships from the University of Aberdeen to AP, DL. The work was also supported by the Wellcome Trust [www.wellcome.ac.uk], NARG, GDB, AJPB (097377) and GDB (102705); and by the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
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T1 - Hypoxia promotes immune evasion by triggering β-glucan masking on the Candida albicans cell surface via mitochondrial and cAMP-protein kinase A signalling

AU - Pradhan, Arnab

AU - Avelar, Gabriela

AU - Bain, Judith M.

AU - Childers, Delma

AU - Larcombe, Daniel E.

AU - Netea, Mihai G.

AU - Shekhova, Elena

AU - Munro, Carol A.

AU - Brown, Gordon D.

AU - Erwig, Lars

AU - Gow, Neil A. R.

AU - Brown, Alistair J. P.

N1 - We are very grateful to the members of our Iain Fraser Cytometry Centre and Microscopy and Histology Core Facility for their superb help, advice and support. We also thank our generous colleagues in the Candida community, and in particular Ana Traven, Jan Quinn, Guanghua Huang, Suzanne Noble, Donna MacCallum, Liz Johnson, Karl Kuchler, Patrick van Dijck, Rich Calderone and Malcolm Whiteway for providing strains used in this study. This work was funded by grants from the UK Medical Research Council [www.mrc.ac.uk], to AJPB, NARG, LPE, MN (MR/M026663/1), and by PhD studentships from the University of Aberdeen to AP, DL. The work was also supported by the Wellcome Trust [www.wellcome.ac.uk], NARG, GDB, AJPB (097377) and GDB (102705); and by the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2018/11/6

Y1 - 2018/11/6

N2 - Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen whilst minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonise hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans, Candida albicans, includes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow derived macrophages and decreased production of IL-10, RANTES and TNFα by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect upon C. albicans host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signalling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ and upc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed by goa1Δ and upc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δ tpk2Δ) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing β-glucan masking via a mitochondrial-cAMP-PKA signalling pathway, thereby modulating local immune responses and promoting fungal colonisation.

AB - Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen whilst minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonise hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans, Candida albicans, includes changes in cell wall structure and reduced exposure, at the cell surface, of β-glucan, a key pathogen associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow derived macrophages and decreased production of IL-10, RANTES and TNFα by peripheral blood mononuclear cells, suggesting that hypoxia-induced β-glucan masking has a significant effect upon C. albicans host interactions. We show that hypoxia-induced β-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signalling. The decrease in β-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Δ and upc2Δ) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Δ). Furthermore, β-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Δ). The β-glucan masking defects displayed by goa1Δ and upc2Δ cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Δ) or PKA (tpk1Δ tpk2Δ) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing β-glucan masking via a mitochondrial-cAMP-PKA signalling pathway, thereby modulating local immune responses and promoting fungal colonisation.

KW - hypoxia

KW - candida albicans

KW - cell-wall

KW - β-glucan masking

KW - mitochondrial signalling

KW - cAMP-protein kinase A signalling

U2 - 10.1128/mBio.01318-18

DO - 10.1128/mBio.01318-18

M3 - Article

VL - 9

JO - mBio

JF - mBio

SN - 2161-2129

M1 - e01318-18

ER -