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

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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 statusPublished - 2018

Keywords

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

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