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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.


B. quintana LPS suppressed LPS/D-galactosamine-induced lethal endotoxaemia.C57/Bl6 mice were i.p. injected with either PBS (n = 20) or 100 μg B. quintana LPS (n = 20). After 30 minutes 10 mice of each group were injected i.p. with PBS and 10 mice were injected i.p. with E. coli LPS (1 μg) + D-galactosamine (14 mg). Survival was monitored for 10 days. (A) Survival rate. (B) Area under the curve. ***p < 0.01, one-way ANOVA test.
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f7: B. quintana LPS suppressed LPS/D-galactosamine-induced lethal endotoxaemia.C57/Bl6 mice were i.p. injected with either PBS (n = 20) or 100 μg B. quintana LPS (n = 20). After 30 minutes 10 mice of each group were injected i.p. with PBS and 10 mice were injected i.p. with E. coli LPS (1 μg) + D-galactosamine (14 mg). Survival was monitored for 10 days. (A) Survival rate. (B) Area under the curve. ***p < 0.01, one-way ANOVA test.

Mentions: To explore whether B. quintana LPS can be used for in vivo studies to neutralize TLR4, we administered B. quintana LPS in an endotoxemia model. B. quintana LPS was injected 30 minutes before a sub-lethal dose of E. coli LPS was injected in combination with D-galactosamine. One single injection of B. quintana LPS revealed to be protective as can be seen in Fig. 7A,B. In contrast to the LPS/D-galactosamine group (30% survival after 10 days), B. quintana LPS administration had a significant higher survival rate (60%). As expected, injection of 100 μg B. quintana LPS alone had no detrimental effect on the survival of the mice.


Bartonella quintana lipopolysaccharide (LPS): structure and characteristics of a potent TLR4 antagonist for in-vitro and in-vivo applications
B. quintana LPS suppressed LPS/D-galactosamine-induced lethal endotoxaemia.C57/Bl6 mice were i.p. injected with either PBS (n = 20) or 100 μg B. quintana LPS (n = 20). After 30 minutes 10 mice of each group were injected i.p. with PBS and 10 mice were injected i.p. with E. coli LPS (1 μg) + D-galactosamine (14 mg). Survival was monitored for 10 days. (A) Survival rate. (B) Area under the curve. ***p < 0.01, one-way ANOVA test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: B. quintana LPS suppressed LPS/D-galactosamine-induced lethal endotoxaemia.C57/Bl6 mice were i.p. injected with either PBS (n = 20) or 100 μg B. quintana LPS (n = 20). After 30 minutes 10 mice of each group were injected i.p. with PBS and 10 mice were injected i.p. with E. coli LPS (1 μg) + D-galactosamine (14 mg). Survival was monitored for 10 days. (A) Survival rate. (B) Area under the curve. ***p < 0.01, one-way ANOVA test.
Mentions: To explore whether B. quintana LPS can be used for in vivo studies to neutralize TLR4, we administered B. quintana LPS in an endotoxemia model. B. quintana LPS was injected 30 minutes before a sub-lethal dose of E. coli LPS was injected in combination with D-galactosamine. One single injection of B. quintana LPS revealed to be protective as can be seen in Fig. 7A,B. In contrast to the LPS/D-galactosamine group (30% survival after 10 days), B. quintana LPS administration had a significant higher survival rate (60%). As expected, injection of 100 μg B. quintana LPS alone had no detrimental effect on the survival of the mice.

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.