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Extracellular ATP released from Candida albicans activates non-peptidergic neurons to augment host defense

Tara N Edwards, Shiqun Zhang, View ORCID ProfileAndrew Liu, Jonathan A. Cohen, View ORCID ProfilePaul Yifan Zhou, Selene Mogavero, View ORCID ProfileBernhard Hube, View ORCID ProfileJudith Berman, Marie-Elisabeth Bougnoux, View ORCID ProfileAlicia R. Mathers, View ORCID ProfileSarah L. Gaffen, Kathryn M. Albers, H. Richard Koerber, Brian M. Davis, Christophe D’Enfert, View ORCID ProfileDaniel H Kaplan
doi: https://doi.org/10.1101/2020.01.27.921049
Tara N Edwards
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Shiqun Zhang
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Andrew Liu
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Jonathan A. Cohen
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Paul Yifan Zhou
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Selene Mogavero
2Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
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Bernhard Hube
2Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
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Judith Berman
3School of Molecular Cell Biology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel
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Marie-Elisabeth Bougnoux
4Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC2019 INRA, Paris, France
5Unité de Parasitologie-Mycologie, Service de Microbiologie clinique, Hôpital Necker-Enfants-Malades, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France
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Alicia R. Mathers
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Sarah L. Gaffen
6Division of Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Kathryn M. Albers
7Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
8Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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H. Richard Koerber
7Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
8Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Brian M. Davis
7Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
8Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Christophe D’Enfert
4Unité Biologie et Pathogénicité Fongiques, Département de Mycologie, Institut Pasteur, USC2019 INRA, Paris, France
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Daniel H Kaplan
1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • For correspondence: dankaplan@pitt.edu
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Abstract

Intestinal microbes release ATP to modulate local immune responses. Herein we demonstrates that Candida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion from C. albicans varied between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by non-peptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca2+ when exposed to supernatant from heat-killed C. albicans (HKCA), and these non-peptidergic fibers are the dominant subset that respond to HKCA. Ca2+ flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase. To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for those C. albicans strains with high ATP secretion. Taken together, our findings indicate that C. albicans releases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses.

Author Summary Bacterial release of ATP has been shown to modulate immune responses. Candida albicans displays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates. C. albicans strains with high ATP secretion show lower fungal burden following epicutaneous infection. Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killed C. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection when exposed to high but not low ATP-secreting isolates of C. albicans. Taken together, our findings indicate that C. albicans releases ATP which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses.

Bullet points

  • ATP released from heat killed C. albicans activates non-peptidergic sensory neurons

  • Live C. albicans clinical isolates release variable amounts of ATP

  • Elevated levels of ATP released by C. albicans correlates with reduced infectivity in vivo

  • MRGPRD-expressing cutaneous neurons are required for defense against ATP-secreting C. albicans

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 28, 2020.
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Extracellular ATP released from Candida albicans activates non-peptidergic neurons to augment host defense
Tara N Edwards, Shiqun Zhang, Andrew Liu, Jonathan A. Cohen, Paul Yifan Zhou, Selene Mogavero, Bernhard Hube, Judith Berman, Marie-Elisabeth Bougnoux, Alicia R. Mathers, Sarah L. Gaffen, Kathryn M. Albers, H. Richard Koerber, Brian M. Davis, Christophe D’Enfert, Daniel H Kaplan
bioRxiv 2020.01.27.921049; doi: https://doi.org/10.1101/2020.01.27.921049
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Extracellular ATP released from Candida albicans activates non-peptidergic neurons to augment host defense
Tara N Edwards, Shiqun Zhang, Andrew Liu, Jonathan A. Cohen, Paul Yifan Zhou, Selene Mogavero, Bernhard Hube, Judith Berman, Marie-Elisabeth Bougnoux, Alicia R. Mathers, Sarah L. Gaffen, Kathryn M. Albers, H. Richard Koerber, Brian M. Davis, Christophe D’Enfert, Daniel H Kaplan
bioRxiv 2020.01.27.921049; doi: https://doi.org/10.1101/2020.01.27.921049

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