Role of lipoteichoic acid in the phagocyte response to group B streptococcus.
Group B Streptococcus (GBS) cell walls potently activate phagocytes by a largely TLR2-independent mechanism. In contrast, the cell wall component lipoteichoic acid (LTA) from diverse Gram-positive bacterial species has been shown to engage TLR2. In this study we examined the role of LTA from GBS in phagocyte activation and the requirements for TLR-LTA interaction. Using cells from knockout mice and genetic complementation in epithelial cells we found that highly pure LTA from both GBS and Staphylococcus aureus interact with TLR2 and TLR6, but not TLR1, in contrast to previous reports. Furthermore, NF-kappaB activation by LTA required the integrity of two putative PI3K binding domains within TLR2 and was inhibited by wortmannin, indicating an essential role for PI3K in cellular activation by LTA. However, LTA from GBS proved to be a relatively weak stimulus of phagocytes containing approximately 20% of the activity observed with LTA from Staphylococcus aureus. Structural analysis by nuclear magnetic resonance spectrometry revealed important differences between LTA from GBS and S. aureus, specifically differences in glycosyl linkage, in the glycolipid anchor and a lack of N-acetylglucosamine substituents of the glycerophosphate backbone. Furthermore, GBS expressing LTA devoid of d-alanine residues, that are essential within immune activation by LTA, exhibited similar inflammatory potency as GBS with alanylated LTA. In conclusion, LTA from GBS is a TLR2/TLR6 ligand that might contribute to secreted GBS activity, but does not contribute significantly to GBS cell wall mediated macrophage activation.
Henneke
Philipp
P
Zentrum für Kinderheilkunde und Jugendmedizin, Albert-Ludwigs Universität Freiburg, Freiburg, Germany. henneke@kikli.ukl.uni-freiburg.de
Morath
Siegfried
S
Uematsu
Satoshi
S
Weichert
Stefan
S
Pfitzenmaier
Markus
M
Takeuchi
Osamu
O
Müller
Andrea
A
Poyart
Claire
C
Akira
Shizuo
S
Berner
Reinhard
R
Teti
Giuseppe
G
Geyer
Armin
A
Hartung
Thomas
T
Trieu-Cuot
Patrick
P
Kasper
Dennis L
DL
Golenbock
Douglas T
DT
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000276:immunology; D013292:Streptococcus agalactiae / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013682:Teichoic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D014443:Tyrosine / Q000737:chemistry
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495368:TLR6 protein, human; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D014443:Tyrosine; C009900:lipoteichoic acid; D000409:Alanine