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  • EMBO reports: 19 (12)

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The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size

Katharina Fuchs, Yamel Cardona Gloria, Olaf‐Oliver Wolz, Franziska Herster, Lokesh Sharma, Carly A Dillen, Christoph Täumer, Sabine Dickhöfer, Zsofia Bittner, Truong‐Minh Dang, Anurag Singh, Daniel Haischer, Maria A Schlöffel, Kirsten J Koymans, Tharmila Sanmuganantham, Milena Krach, Thierry Roger, Didier Le Roy, Nadine A Schilling, Felix Frauhammer, Lloyd S Miller, Thorsten Nürnberger, Salomé LeibundGut‐Landmann, View ORCID ProfileAndrea A Gust, Boris Macek, Martin Frank, Cécile Gouttefangeas, Charles S Dela Cruz, Dominik Hartl, View ORCID ProfileAlexander NR Weber
DOI 10.15252/embr.201846065 | Published online 18.10.2018
EMBO reports (2018) 19, e46065
Katharina Fuchs
Department of Immunology, University of Tübingen, Tübingen, Germany
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Yamel Cardona Gloria
Department of Immunology, University of Tübingen, Tübingen, Germany
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Olaf‐Oliver Wolz
Department of Immunology, University of Tübingen, Tübingen, Germany
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Franziska Herster
Department of Immunology, University of Tübingen, Tübingen, Germany
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Lokesh Sharma
Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Microbial Pathogenesis, Center for Pulmonary Infection Research and Infection (CPIRT), New Haven, CT, USA
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Carly A Dillen
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Christoph Täumer
Department of Quantitative Proteomics and Proteome Center, University of Tübingen, Tübingen, Germany
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Sabine Dickhöfer
Department of Immunology, University of Tübingen, Tübingen, Germany
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Zsofia Bittner
Department of Immunology, University of Tübingen, Tübingen, Germany
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Truong‐Minh Dang
Department of Immunology, University of Tübingen, Tübingen, Germany
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Anurag Singh
University Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany
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Daniel Haischer
Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
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Maria A Schlöffel
Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
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Kirsten J Koymans
Department of Medical Microbiology, University Medical Center Utrecht, CX Utrecht, The Netherlands
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Tharmila Sanmuganantham
Department of Immunology, University of Tübingen, Tübingen, Germany
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Milena Krach
Department of Immunology, University of Tübingen, Tübingen, Germany
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Thierry Roger
Infectious Diseases Service, Lausanne University Hospital, Epalinges, Switzerland
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Didier Le Roy
Infectious Diseases Service, Lausanne University Hospital, Epalinges, Switzerland
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Nadine A Schilling
Institute of Organic Chemistry, University of Tübingen, Tübingen, Germany
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Felix Frauhammer
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Dermatology, Heidelberg University, Heidelberg, Germany
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Lloyd S Miller
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Thorsten Nürnberger
Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
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Salomé LeibundGut‐Landmann
Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
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Andrea A Gust
Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
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Boris Macek
Department of Quantitative Proteomics and Proteome Center, University of Tübingen, Tübingen, Germany
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Martin Frank
Biognos AB, Göteborg, Sweden
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Cécile Gouttefangeas
Department of Immunology, University of Tübingen, Tübingen, Germany
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Charles S Dela Cruz
Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Microbial Pathogenesis, Center for Pulmonary Infection Research and Infection (CPIRT), New Haven, CT, USA
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Dominik Hartl
University Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, GermanyRoche Pharma Research & Early Development (pRED), Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
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Alexander NR Weber
Department of Immunology, University of Tübingen, Tübingen, Germany
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Author Affiliations

  1. Katharina Fuchs1,†,
  2. Yamel Cardona Gloria1,†,
  3. Olaf‐Oliver Wolz1,
  4. Franziska Herster1,
  5. Lokesh Sharma2,
  6. Carly A Dillen3,
  7. Christoph Täumer4,
  8. Sabine Dickhöfer1,
  9. Zsofia Bittner1,
  10. Truong‐Minh Dang1,
  11. Anurag Singh5,
  12. Daniel Haischer6,
  13. Maria A Schlöffel6,
  14. Kirsten J Koymans7,
  15. Tharmila Sanmuganantham1,
  16. Milena Krach1,
  17. Thierry Roger8,
  18. Didier Le Roy8,
  19. Nadine A Schilling9,
  20. Felix Frauhammer10,11,
  21. Lloyd S Miller3,
  22. Thorsten Nürnberger6,
  23. Salomé LeibundGut‐Landmann12,
  24. Andrea A Gust6,
  25. Boris Macek4,
  26. Martin Frank13,
  27. Cécile Gouttefangeas1,
  28. Charles S Dela Cruz2,
  29. Dominik Hartl5,14 and
  30. Alexander NR Weber (alexander.weber{at}uni-tuebingen.de)*,1
  1. 1Department of Immunology, University of Tübingen, Tübingen, Germany
  2. 2Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Microbial Pathogenesis, Center for Pulmonary Infection Research and Infection (CPIRT), New Haven, CT, USA
  3. 3Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  4. 4Department of Quantitative Proteomics and Proteome Center, University of Tübingen, Tübingen, Germany
  5. 5University Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany
  6. 6Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany
  7. 7Department of Medical Microbiology, University Medical Center Utrecht, CX Utrecht, The Netherlands
  8. 8Infectious Diseases Service, Lausanne University Hospital, Epalinges, Switzerland
  9. 9Institute of Organic Chemistry, University of Tübingen, Tübingen, Germany
  10. 10Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  11. 11Department of Dermatology, Heidelberg University, Heidelberg, Germany
  12. 12Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
  13. 13Biognos AB, Göteborg, Sweden
  14. 14Roche Pharma Research & Early Development (pRED), Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
  1. ↵*Corresponding author. Tel: +49 7071 29 87623; Fax: +49 7071 29 4579; E‐mail: alexander.weber{at}uni-tuebingen.de
  1. ↵† These authors contributed equally to this work

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Abstract

Chitin is the second most abundant polysaccharide in nature and linked to fungal infection and asthma. However, bona fide immune receptors directly binding chitin and signaling immune activation and inflammation have not been clearly identified because polymeric crude chitin with unknown purity and molecular composition has been used. By using defined chitin (N‐acetyl‐glucosamine) oligomers, we here identify six‐subunit‐long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll‐like receptor (TLR2) as a primary fungal chitin sensor on human and murine immune cells. Chitin oligomers directly bind TLR2 with nanomolar affinity, and this fungal TLR2 ligand shows overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Unexpectedly, chitin oligomers composed of five or less subunits are inactive, hinting to a size‐dependent system of immuno‐modulation that appears conserved in plants and humans. Since blocking of the chitin‐TLR2 interaction effectively prevents chitin‐mediated inflammation in vitro and in vivo, our study highlights the chitin‐TLR2 interaction as a potential target for developing novel therapies in chitin‐related pathologies and fungal disease.

Synopsis

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Chitin, a polysaccharide linked to fungal infection and allergic asthma, directly binds to the innate immune receptor TLR2 and triggers inflammation dependent on oligomer size. Blocking the chitin‐TLR2 interaction effectively prevents chitin‐mediated inflammation.

  • Oligomeric chains of fungal chitin directly bind to TLR2 and trigger inflammation.

  • Blocking of the chitin‐TLR2 interaction prevents chitin‐mediated inflammation in vitro and in vivo.

  • Size‐dependent chitin recognition based on oligomers is found in both plants and humans.

  • anti‐fungal innate immunity
  • chitin
  • inflammation
  • N‐acetyl‐glucosamine
  • toll‐like receptor

EMBO Reports (2018) 19: e46065

  • Received March 6, 2018.
  • Revision received August 31, 2018.
  • Accepted September 10, 2018.
  • © 2018 The Authors
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Volume 19, Issue 12
01 December 2018
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