Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia

Fischer, Mike; Spies-Weisshart, Baerbel; Schrenk, Karin; Gruhn, Bernd; Wittig, Susan; Glaser, Anita; Hochhaus, Andreas; Scholl, Sebastian; Schnetzke, Ulf

doi:10.1371/journal.pone.0150632

Cited by 36 publications

(39 citation statements)

References 30 publications

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“…Our study now dispels these ambiguities and provides unequivocal experimental evidence for TLR2 as a molecular chitin immune receptor. Our results now provide a missing molecular link between fungal infection and the previously observed dependence on TLR2 in murine fungal infection models (Cunha et al, 2010;Goodridge & Underhill, 2008) and, importantly, in patients with the functional rs5743708 (p.753RQ) TLR2 allele (Fischer et al, 2016;Woehrle et al, 2008). Of note, the effect of SSL3 on chitin sensing warrants further analysis in S. aureus/C.…”

Section: Discussionsupporting

confidence: 55%

“…To gain additional evidence for TLR2-dependence of chitin recognition in humans, we analyzed whole blood from healthy individuals without (WT p.753RR) and with heterozygous carriage of a well-known TLR2 gene variant, rs5743708 (p.753RQ). This variant is strongly associated with pulmonary invasive fungal disease in acute myeloid leukemia patients (OR 4.5, 95% CI 1.4-15.1, p = 0.014, see (Fischer et al, 2016)) and with up to 40-fold altered cytokine levels during Candida sepsis, respectively (Woehrle et al, 2008). Similarly to the mycobacterial TLR2 agonist Pam2, but not to the TLR8 agonist R848, stimulation with C10-15 showed a 100% higher induction of relative IL10 transcription between 753RR and 753QR allele groups, (Fig.…”

Section: Oligomeric Chitin Sensing Depends On Tlr2mentioning

confidence: 99%

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

Fuchs

Gloria

Wolz

et al. 2018

Preprint

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Chitin is a highly abundant polysaccharide and linked to fungal infection and asthma. Unfortunately, its polymeric structure has hampered the identification of immune receptors directly binding chitin and signaling immune activation and inflammation, because purity, molecular structure and molarity are not well definable for a polymer typically extracted from biomass. Therefore, by using defined chitin (N-acetyl-glucosamine) oligomers, we identified six subunit long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR) 2 as the primary fungal chitin receptor on human and murine immune cells. Chitin oligomers directly bound TLR2 with nanomolar affinity and showed both overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Conversely, chitin oligomers shorter than 6 subunits were inactive or showed antagonistic effects on chitin/TLR2-mediated signaling, hinting to a sizedependent sensing/activation system unexpectedly conserved in plants and humans. Since blocking the chitin-TLR2 interaction effectively prevented 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. Fuchs

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Section: Discussionsupporting

confidence: 55%

Section: Oligomeric Chitin Sensing Depends On Tlr2mentioning

confidence: 99%

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

Fuchs

Gloria

Wolz

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…TLR2 seems to cooperate with TLR1 in agreement with , but possibly an additional receptor contributes to full activation. Our results provide a missing molecular link between fungal infection and the previously observed dependence on TLR2 in murine fungal infection models and, importantly, in patients with the functional rs5743708 (p.753RQ) TLR2 allele . Of note, the effect of SSL3 on chitin sensing warrants further analysis in S. aureus/C.…”

Section: Resultsmentioning

confidence: 52%

“…with the functional rs5743708 (p.753RQ) TLR2 allele [23,24]. Of note, the effect of SSL3 on chitin sensing warrants further analysis in S. aureus/C.…”

Section: Interference With Chitin-tlr2 Binding Suppresses Chitinmediamentioning

confidence: 98%

The fungal ligand chitin directly binds TLR 2 and triggers inflammation dependent on oligomer size

et al. 2018

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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.

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“…. We and others identified additional Dectin‐1 polymorphisms that predispose to fungal infections in hematological patients .…”

Section: Discussionmentioning

confidence: 67%

Isoform localization of Dectin‐1 regulates the signaling quality of anti‐fungal immunity

et al. 2017

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Dectin-1 is recognized as a major receptor for fungal ß-glucans and contributes to anti-fungal immunity. Human monocyte populations express Dectin-1 isoforms A and B, which differ by the presence of a stalk region and its N-linked glycosylation site. Here, we analyzed the expression of both isoforms in human monocyte-derived cells. The cellular localization on cell lines stably expressing either Dectin-1 isoform A or B was studied by flow cytometry and confocal laser scanning microscopy. Intracellular protein signaling and cytokine production were analyzed by immunoblotting and cytometric bead array, respectively. Monocyte-derived cells showed cell type-specific expression of the two isoforms. Glycosylated Dectin-1 isoform A was predominantly localized at the cell surface, non-glycosylated isoform B was retained intracellularly. Inhibition of glycosylation resulted in efficient abrogation of cell surface expression of isoform A. Signaling quality following Dectin-1 stimulation was reduced in isoform B cells. Differential isoform specific cytokine secretion was observed by cytometric bead array. We show here that n-glycosylation of Dectin-1 is crucial for its cell surface expression and consequently signal transduction. Taken together, unique cytokine secretion and varying expression levels of human Dectin-1 isoforms on monocyte-derived cells may indicate distinct isoform usage as a cell type-specific mechanism of regulating anti-fungal immunity.

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Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia

Cited by 36 publications

References 30 publications

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

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

The fungal ligand chitin directly binds TLR 2 and triggers inflammation dependent on oligomer size

Isoform localization of Dectin‐1 regulates the signaling quality of anti‐fungal immunity

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