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

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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.


Small-angle X-ray scattering pattern of LPS from B. quintana at 20 and 40 °C.The logarithm of the scattering intensity log I is plotted versus the scattering vector s = 1/d (d spacings of the reflections.
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f9: Small-angle X-ray scattering pattern of LPS from B. quintana at 20 and 40 °C.The logarithm of the scattering intensity log I is plotted versus the scattering vector s = 1/d (d spacings of the reflections.

Mentions: To determine the aggregate structure of B. quintana LPS, small-angle X-ray scattering (SAXS) at the Hamburg synchrotron source PETRA was applied. For this, LPS at a concentration of 1 mg/50 μl was analyzed at two temperatures 20 and 40 °C (Fig. 9). The scattering patterns are indicative of a main maximum at d = 6.67 and 6.29 nm for 20 and 40 °C, respectively, and further reflections each at d/2, d/3, and d/5, which can be assigned to a multi-lamellar aggregate structure of the LPS dispersion.


Bartonella quintana lipopolysaccharide (LPS): structure and characteristics of a potent TLR4 antagonist for in-vitro and in-vivo applications
Small-angle X-ray scattering pattern of LPS from B. quintana at 20 and 40 °C.The logarithm of the scattering intensity log I is plotted versus the scattering vector s = 1/d (d spacings of the reflections.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: Small-angle X-ray scattering pattern of LPS from B. quintana at 20 and 40 °C.The logarithm of the scattering intensity log I is plotted versus the scattering vector s = 1/d (d spacings of the reflections.
Mentions: To determine the aggregate structure of B. quintana LPS, small-angle X-ray scattering (SAXS) at the Hamburg synchrotron source PETRA was applied. For this, LPS at a concentration of 1 mg/50 μl was analyzed at two temperatures 20 and 40 °C (Fig. 9). The scattering patterns are indicative of a main maximum at d = 6.67 and 6.29 nm for 20 and 40 °C, respectively, and further reflections each at d/2, d/3, and d/5, which can be assigned to a multi-lamellar aggregate structure of the LPS dispersion.

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.