TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides

TLDR

Bacterial cell walls contain lipoproteins/peptides that strongly modulate innate immunity, and triacylated lipopeptides are thought to signal via TLR2/TLR1 while diacylated ones use TLR2/TLR6. The authors demonstrate that both di‑ and triacylated lipopeptides activate TLR2 signaling independently of TLR1 or TLR6, with triacylation necessary but not sufficient for TLR1 dependence and diacylation similarly for TLR6, and that distinct lipopeptides are recognized by TLR2 without requiring the canonical coreceptors.

Abstract

Bacterial cell walls contain lipoproteins/peptides, which are strong modulators of the innate immune system. Triacylated lipopeptides are assumed to be recognized by TLR2/TLR1-, whereas diacylated lipopeptides use TLR2/TLR6 heteromers for signaling. Following our initial discovery of TLR6-independent diacylated lipopeptides, we could now characterize di- and triacylated lipopeptides (e.g. Pam(2)C-SK(4), Pam(3)C-GNNDESNISFKEK), which have stimulatory activity in TLR1- and in TLR6-deficient mice. Furthermore, for the first time, we present triacylated lipopeptides with short length ester-bound fatty acids (like PamOct(2)C-SSNASK(4)), which induce no response in TLR1-deficient cells. No differences in the phosphorylation of MAP kinases by lipopeptide analogs having different TLR2-coreceptor usage were observed. Blocking experiments indicated that different TLR2 heteromers recognize their specific lipopeptide ligands independently from each other. In summary, a triacylation pattern is necessary but not sufficient to render a lipopeptide TLR1-dependent, and a diacylation pattern is necessary but not sufficient to render a lipopeptide TLR6-dependent. Contrary to the current model, distinct lipopeptides are recognized by TLR2 in a TLR1- and TLR6-independent manner.