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Lactate signalling regulates fungal β-glucan masking and immune evasion

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Abstract

As they proliferate, fungi expose antigens at their cell surface that are potent stimulators of the innate immune response, and yet the commensal fungus Candida albicans is able to colonize immuno competent individuals. We show that C. albicans may evade immune detection by presenting a moving immunological target. We report that the exposure of β-glucan, a key pathogen-associated molecular pattern (PAMP) located at the cell surface of C. albicans and other pathogenic Candida species, is modulated in response to changes in the carbon source. Exposure to lactate induces β-glucan masking in C. albicans via a signalling pathway that has recruited an evolutionarily conserved receptor (Gpr1) and transcriptional factor (Crz1) from other well-characterized pathways. In response to lactate, these regulators control the expression of cell-wall-related genes that contribute to β-glucan masking. This represents the first description of active PAMP masking by a Candida species, a process that reduces the visibility of the fungus to the immune system.

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Figure 1: Lactate activates β-glucan masking in Candida and attenuates the phagocytic response.
Figure 2: Lactate-induced β-glucan masking is specific, physiologically relevant and mediated by Gpr1.
Figure 3: Lactate-induced β-glucan masking is dependent on Crz1, but not calcineurin.
Figure 4: Role of lactate-regulated genes in lactate-dependent β-glucan masking.
Figure 5: Regulation of β-glucan masking in C. albicans.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

The authors apologize to colleagues whose work we have been unable to cite because of space constraints. The authors thank F. Odds for access to his collection of clinical isolates. The authors thank R. Yuecel and L. Duncan in the Iain Fraser Cytometry Centre (Aberdeen University), and L. Wight and K. MacKenzie in the Microscopy and Histology Core Facility (Aberdeen University) for their expert help with the cytometry and microscopy experiments. The authors acknowledge the assistance of staff at the University of Aberdeen Medical Research Facility, and B. Martin in the Centre for Genome Enabled Biology and Medicine (Aberdeen University) for help with the RNA sequencing. A.J.P.B. was supported by the European Research Council (STRIFE, ERC-2009-AdG-249793), the UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1) and the Wellcome Trust (080088; 097377). E.R.B. was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1), G.M.A. by CNPq-Brazil (Science without Borders fellowship 202976/2014–9), G.D.B. by the Wellcome Trust (102705), C.A.M. by the UK Medical Research Council (G0400284), D.M.M. by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1), N.A.R.G. and J.W. by the Wellcome Trust (086827, 075470 and 101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). This work was also supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). All animal experiments were performed under UK Home Office project licence PPL 60/4135 (granted to D.M.M.) in accordance with Home Office ethical guidelines.

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E.R.B., D.S.C., G.M.A. and A.J.P.B. planned the experiments. E.R.B., G.M.A., D.S.C., J.M., J.M.B., J.W., M.D.P. and D.M.M. performed the experiments. Animal experiments were performed by D.M.M., E.R.B. and S.E.H. S.L.K. and E.R.B performed bioinformatic analyses. S.E.H., L.A.W., L.P.E., C.A.M., N.A.R.G. and G.D.B. provided materials and insight during this study. E.R.B. and A.J.P.B. drafted the manuscript with contributions from J.M., G.M.A., D.S.C., J.M.B., C.A.M., N.A.R.G., G.D.B. and D.M.M.

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Correspondence to Alistair J. P. Brown.

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Ballou, E., Avelar, G., Childers, D. et al. Lactate signalling regulates fungal β-glucan masking and immune evasion. Nat Microbiol 2, 16238 (2017). https://doi.org/10.1038/nmicrobiol.2016.238

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