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EMBO Rep. 2018 Dec;19(12). pii: e46065. doi: 10.15252/embr.201846065. Epub 2018 Oct 18.

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

Author information

1
Department of Immunology, University of Tübingen, Tübingen, Germany.
2
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.
3
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Department of Quantitative Proteomics and Proteome Center, University of Tübingen, Tübingen, Germany.
5
University Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany.
6
Center for Plant Molecular Biology, University of Tübingen, Tübingen, Germany.
7
Department of Medical Microbiology, University Medical Center Utrecht, CX Utrecht, The Netherlands.
8
Infectious Diseases Service, Lausanne University Hospital, Epalinges, Switzerland.
9
Institute of Organic Chemistry, University of Tübingen, Tübingen, Germany.
10
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Department of Dermatology, Heidelberg University, Heidelberg, Germany.
12
Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
13
Biognos AB, Göteborg, Sweden.
14
Roche Pharma Research & Early Development (pRED), Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland.
15
Department of Immunology, University of Tübingen, Tübingen, Germany alexander.weber@uni-tuebingen.de.

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.

KEYWORDS:

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

PMID:
30337494
PMCID:
PMC6280652
[Available on 2019-12-01]
DOI:
10.15252/embr.201846065
[Indexed for MEDLINE]

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