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Zusammenfassung:
Toll-like receptor 5 (TLR5) is a Pattern Recognition Receptor which targets and responds to a conserved site on bacterial flagellin, the protein subunit of bacterial flagella, which confers motility. TLR5-flagellin has widely been used as a proxy for immune activity. However, we recently identified a class of flagellins termed "silent", which contain the TLR5 epitope allowing binding at the canonical binding site, but elicit a weak immune response. To better characterise the relationship between binding at the TLR5 epitope and signalling, we determined the relative binding and activity profiles of 116 flagellins with the TLR5 epitope against a truncated human TLR5 construct, containing epitope binding site. Our results decoupled binding and subsequent immune activity. We found a continuum in binding strengths within TLR5 epitope-containing flagellins, with individual binding profiles correlating only weakly to immune activity. Further structural, kinetic, and biochemical studies on individual flagellins indicated that interactions with separate allosteric TLR5-binding regions are essential in triggering a strong response. This discovery represents a new mechanism for evasion of innate immune activation, potentially leading to new avenues for developing TLR5-targetted treatments.
