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Bartonella quintana lipopolysaccharide (LPS): structure and characteristics of a potent TLR4 antagonist for in-vitro and in-vivo applications

View Article: PubMed Central - PubMed

ABSTRACT

The pattern recognition receptor TLR4 is well known as a crucial receptor during infection and inflammation. Several TLR4 antagonists have been reported to inhibit the function of TLR4. Both natural occurring antagonists, lipopolysaccharide (LPS) from Gram-negative bacteria as well as synthetic compounds based on the lipid A structure of LPS have been described as potent inhibitors of TLR4. Here, we have examined the characteristics of a natural TLR4 antagonist, isolated from Bartonella quintana bacterium by elucidating its chemical primary structure. We have found that this TLR4 antagonist is actually a lipooligosaccharide (LOS) instead of a LPS, and that it acts very effective, with a high inhibitory activity against triggering by the LPS-TLR4 system in the presence of a potent TLR4 agonist (E. coli LPS). Furthermore, we demonstrate that B. quintana LPS is not inactivated by polymyxin B, a classical cyclic cationic polypeptide antibiotic that bind the lipid A part of LPS, such as E. coli LPS. Using a murine LPS/D-galactosamine endotoxaemia model we showed that treatment with B. quintana LPS could improve the survival rate significantly. Since endogenous TLR4 ligands have been associated with several inflammatory- and immune-diseases, B. quintana LPS might be a novel therapeutic strategy for TLR4-driven pathologies.

No MeSH data available.


Proposed structure of B. quintana LPS.The primary sequence was depicted by Zähringer et al.57 for the equivalent molecule of B. henselae. Gas chromatographic analysis and mass spectrometry present differences of the B. quintana in comparison to the B. henselae LPS in the sugar composition and the acyl chains. The former contains a N-acetylated hexose in the outer core, while for the latter a hexose is described. Furthermore, one of the 3-OH C12 fatty acids is unsaturated in the LPS of B. quintana. For both substitutions the structures are not elucidated yet and the drawing shows only one of several possible positions.
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f8: Proposed structure of B. quintana LPS.The primary sequence was depicted by Zähringer et al.57 for the equivalent molecule of B. henselae. Gas chromatographic analysis and mass spectrometry present differences of the B. quintana in comparison to the B. henselae LPS in the sugar composition and the acyl chains. The former contains a N-acetylated hexose in the outer core, while for the latter a hexose is described. Furthermore, one of the 3-OH C12 fatty acids is unsaturated in the LPS of B. quintana. For both substitutions the structures are not elucidated yet and the drawing shows only one of several possible positions.

Mentions: In order to elucidate the structure of B. quintana LPS we performed gas liquid chromatography and mass spectrometry (GLC-MS) and electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) analysis. The LPS of B. quintana appears in the MS analysis with a molecular mass of 2438,448 Dalton. By examining fragmentation products of 30 V spectra it reveals that the sugar composition of B. quintana LPS contains 2 Kdo, 1 HexNAc and 2 HexN. The lipids were further characterized by GLC-M and the fatty acids 25-OH C26:0, 2 3-OH C16:0, 3-OH C12:0 and 3-OH C12:1 were detected. Figure 8 showed the predicted structure of B. quintana LPS and it reveals that the TLR4 antagonist is actually a lipooligosaccharide (LOS).


Bartonella quintana lipopolysaccharide (LPS): structure and characteristics of a potent TLR4 antagonist for in-vitro and in-vivo applications
Proposed structure of B. quintana LPS.The primary sequence was depicted by Zähringer et al.57 for the equivalent molecule of B. henselae. Gas chromatographic analysis and mass spectrometry present differences of the B. quintana in comparison to the B. henselae LPS in the sugar composition and the acyl chains. The former contains a N-acetylated hexose in the outer core, while for the latter a hexose is described. Furthermore, one of the 3-OH C12 fatty acids is unsaturated in the LPS of B. quintana. For both substitutions the structures are not elucidated yet and the drawing shows only one of several possible positions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037446&req=5

f8: Proposed structure of B. quintana LPS.The primary sequence was depicted by Zähringer et al.57 for the equivalent molecule of B. henselae. Gas chromatographic analysis and mass spectrometry present differences of the B. quintana in comparison to the B. henselae LPS in the sugar composition and the acyl chains. The former contains a N-acetylated hexose in the outer core, while for the latter a hexose is described. Furthermore, one of the 3-OH C12 fatty acids is unsaturated in the LPS of B. quintana. For both substitutions the structures are not elucidated yet and the drawing shows only one of several possible positions.
Mentions: In order to elucidate the structure of B. quintana LPS we performed gas liquid chromatography and mass spectrometry (GLC-MS) and electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) analysis. The LPS of B. quintana appears in the MS analysis with a molecular mass of 2438,448 Dalton. By examining fragmentation products of 30 V spectra it reveals that the sugar composition of B. quintana LPS contains 2 Kdo, 1 HexNAc and 2 HexN. The lipids were further characterized by GLC-M and the fatty acids 25-OH C26:0, 2 3-OH C16:0, 3-OH C12:0 and 3-OH C12:1 were detected. Figure 8 showed the predicted structure of B. quintana LPS and it reveals that the TLR4 antagonist is actually a lipooligosaccharide (LOS).

View Article: PubMed Central - PubMed

ABSTRACT

The pattern recognition receptor TLR4 is well known as a crucial receptor during infection and inflammation. Several TLR4 antagonists have been reported to inhibit the function of TLR4. Both natural occurring antagonists, lipopolysaccharide (LPS) from Gram-negative bacteria as well as synthetic compounds based on the lipid A structure of LPS have been described as potent inhibitors of TLR4. Here, we have examined the characteristics of a natural TLR4 antagonist, isolated from Bartonella quintana bacterium by elucidating its chemical primary structure. We have found that this TLR4 antagonist is actually a lipooligosaccharide (LOS) instead of a LPS, and that it acts very effective, with a high inhibitory activity against triggering by the LPS-TLR4 system in the presence of a potent TLR4 agonist (E. coli LPS). Furthermore, we demonstrate that B. quintana LPS is not inactivated by polymyxin B, a classical cyclic cationic polypeptide antibiotic that bind the lipid A part of LPS, such as E. coli LPS. Using a murine LPS/D-galactosamine endotoxaemia model we showed that treatment with B. quintana LPS could improve the survival rate significantly. Since endogenous TLR4 ligands have been associated with several inflammatory- and immune-diseases, B. quintana LPS might be a novel therapeutic strategy for TLR4-driven pathologies.

No MeSH data available.