Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin
is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to During the innate response, IL-17 is produced...
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Published in | Science immunology Vol. 2; no. 17 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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03.11.2017
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Abstract | is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of
hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to
During the innate response, IL-17 is produced by γδ T cells and a poorly understood population of innate-acting CD4
αβ T cell receptor (TCRαβ)
cells, but only the TCRαβ
cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, as evidenced by
mice that report antigen-specific signaling through the TCR. Rather, the expansion of innate TCRαβ
cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However,
mutants that cannot switch from yeast to hyphae showed impaired TCRαβ
cell proliferation and
expression. This prompted us to assess the role of candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Candidalysin-deficient strains failed to up-regulate
or drive the proliferation of innate TCRαβ
cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1α/β and other cytokines. Thus, IL-17 and
, via secreted candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae. |
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AbstractList | is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of
hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to
During the innate response, IL-17 is produced by γδ T cells and a poorly understood population of innate-acting CD4
αβ T cell receptor (TCRαβ)
cells, but only the TCRαβ
cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, as evidenced by
mice that report antigen-specific signaling through the TCR. Rather, the expansion of innate TCRαβ
cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However,
mutants that cannot switch from yeast to hyphae showed impaired TCRαβ
cell proliferation and
expression. This prompted us to assess the role of candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Candidalysin-deficient strains failed to up-regulate
or drive the proliferation of innate TCRαβ
cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1α/β and other cytokines. Thus, IL-17 and
, via secreted candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae. |
Author | McGeachy, Mandy J Biswas, Partha S Huppler, Anna R Coleman, Bianca M Verma, Akash H Ramani, Kritika Kane, Lawrence P Waisman, Ari Gaffen, Sarah L Richardson, Jonathan P Zhou, Chunsheng Mufazalov, Ilgiz A Hube, Bernhard Moyes, David L Naglik, Julian R Ho, Jemima |
Author_xml | – sequence: 1 givenname: Akash H orcidid: 0000-0002-5985-5201 surname: Verma fullname: Verma, Akash H organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 2 givenname: Jonathan P surname: Richardson fullname: Richardson, Jonathan P organization: Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK – sequence: 3 givenname: Chunsheng orcidid: 0000-0002-9721-7948 surname: Zhou fullname: Zhou, Chunsheng organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 4 givenname: Bianca M orcidid: 0000-0003-4276-7456 surname: Coleman fullname: Coleman, Bianca M organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 5 givenname: David L orcidid: 0000-0002-1657-918X surname: Moyes fullname: Moyes, David L organization: Centre for Host-Microbiome Interactions, Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK – sequence: 6 givenname: Jemima orcidid: 0000-0002-2356-9190 surname: Ho fullname: Ho, Jemima organization: Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK – sequence: 7 givenname: Anna R surname: Huppler fullname: Huppler, Anna R organization: Department of Pediatrics, Children's Research Institute, Children's Hospital and Health System, Medical College of Wisconsin, Milwaukee, WI 53226, USA – sequence: 8 givenname: Kritika surname: Ramani fullname: Ramani, Kritika organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 9 givenname: Mandy J surname: McGeachy fullname: McGeachy, Mandy J organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 10 givenname: Ilgiz A orcidid: 0000-0001-9332-0131 surname: Mufazalov fullname: Mufazalov, Ilgiz A organization: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany – sequence: 11 givenname: Ari orcidid: 0000-0003-4304-8234 surname: Waisman fullname: Waisman, Ari organization: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany – sequence: 12 givenname: Lawrence P orcidid: 0000-0001-5198-516X surname: Kane fullname: Kane, Lawrence P organization: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 13 givenname: Partha S surname: Biswas fullname: Biswas, Partha S organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA – sequence: 14 givenname: Bernhard orcidid: 0000-0002-6028-0425 surname: Hube fullname: Hube, Bernhard organization: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany – sequence: 15 givenname: Julian R orcidid: 0000-0002-8072-7917 surname: Naglik fullname: Naglik, Julian R email: sarah.gaffen@pitt.edu, julian.naglik@kcl.ac.uk organization: Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK. sarah.gaffen@pitt.edu julian.naglik@kcl.ac.uk – sequence: 16 givenname: Sarah L orcidid: 0000-0001-8511-2041 surname: Gaffen fullname: Gaffen, Sarah L email: sarah.gaffen@pitt.edu, julian.naglik@kcl.ac.uk organization: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. sarah.gaffen@pitt.edu julian.naglik@kcl.ac.uk |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29101209$$D View this record in MEDLINE/PubMed |
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ContentType | Journal Article |
Copyright | Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. |
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References | 29101210 - Sci Immunol. 2017 Nov 3;2(17):eaao5703. doi: 10.1126/sciimmunol.aao5703 |
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Snippet | is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of
hyphae into oral epithelium is an essential... |
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SubjectTerms | Adaptive Immunity - immunology Animals Candida albicans - immunology Candida albicans - metabolism Candida albicans - physiology Candidiasis - immunology Candidiasis - microbiology Cytokines - immunology Cytokines - metabolism Epithelial Cells - immunology Epithelial Cells - microbiology Female Fungal Proteins - genetics Fungal Proteins - immunology Fungal Proteins - metabolism Humans Hyphae - immunology Hyphae - metabolism Hyphae - physiology Immunity, Innate - immunology Interleukin-17 - genetics Interleukin-17 - immunology Interleukin-17 - metabolism Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mouth Mucosa - immunology Mouth Mucosa - microbiology Virulence Factors - genetics Virulence Factors - immunology Virulence Factors - metabolism |
Title | Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin |
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