Differential recognition of structural details of bacterial lipopeptides by toll-like receptors.
The question which detailed structures of bacterial modulins determine their relative biological activity and respective host cell receptors was examined with synthetic variants of mycoplasmal lipopeptides as model compounds, as well as recombinant outer surface protein A (OspA) of Borrelia burgdorferi and lipoteichoic acid. Mouse fibroblasts bearing genetic deletions of various toll-like receptors (TLR) were the indicator cells to study receptor requirements, primary macrophages served to measure dose response. The following results were obtained: (i) the TLR system discriminates between modulins with three and those with two long-chain fatty acids in their lipid moiety, in that lipopeptides with three fatty acids were recognized by TLR2, whereas those with two long-chain fatty acids and lipoteichoic acid required the additional cooperation with TLR6; (ii) substitution of the free N terminus of mycoplasmal lipopeptides with an acetyl or palmitoyl group decreased the specific activity; (iii) removal of one or both ester-bound fatty acids lowered the specific activity by five orders of magnitude or deleted biological activity; (iv) oxidation of the thioether group lowered the specific activity by at least four orders of magnitude. The implications of these findings for physiological inactivation of lipopeptides and host-bacteria interactions in general are discussed.
Morr
Michael
M
Research Group Molecular Recognition of the Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany.
Takeuchi
Osamu
O
Akira
Shizuo
S
Simon
Markus M
MM
Mühlradt
Peter F
PF
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001898:Borrelia / Q000737:chemistry; D029721:Drosophila Proteins; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D055666:Lipopeptides; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008074:Lipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013682:Teichoic Acids / Q000737:chemistry / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors
D001426:Bacterial Proteins; D029721:Drosophila Proteins; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D013682:Teichoic Acids; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; C009900:lipoteichoic acid; C106335:macrophage stimulatory lipopeptide 2