Epitope shaving promotes fungal immune evasion

Delma S. Childers* (Corresponding Author), Gabriela Mol Avelar, Judith Bain, Arnab Pradhan, Daniel Elliott Larcombe, Mihai G. Netea, Lars P. Erwig, Neil A.R. Gow, Alistair J.P. Brown

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)
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The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as -1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks -1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks -1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced -glucan “masking” pathway to promote -1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all -1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes.
IMPORTANCE The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of -glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed -glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.
Original languageEnglish
Article numbere00984-20
Number of pages13
Issue number4
Early online date7 Jul 2020
Publication statusPublished - 7 Jul 2020

Bibliographical note

A.J.P.B., N.A.R.G., L.P.E., M.G.N.: This work was supported by the UK Medical Research Council (MR/M026663/1) and the Wellcome Trust (097377). N.A.R.G.: Wellcome Trust (075470, 086827, 093378, 099197, 101873, 102705, 200208). A.P., D.E.L.: PhD studentships from the University of Aberdeen. All authors: This work was supported by the MRC Centre for Medical Mycology, the University of Aberdeen, and the University of Exeter (MR/N006364/1). M.G.N. was supported by an ERC Advanced Grant (no. 833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.
All correspondence and requests for materials should be addressed to Delma S.
Childers or Alistair J. P. Brown.
We apologize to colleagues whose work we have been unable to cite because of
space constraints. We are grateful to David Stead and the University of Aberdeen
Proteomics Core Facility, Andrea Holme and the Iain Fraser Cytometry Centre, and Kevin MacKenzie and the Microscopy and Histology Core Facility at Aberdeen University for their expert help with the proteomics, cytometry, and microscopy.


  • Candida Albicans
  • cell wall
  • Xog1 exoglucanase
  • β-glucan shaving;
  • immune Evasion
  • castanospermine
  • virulence


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