Rhizobium Sin-1 Lipopolysaccharide (LPS) Prevents Enteric LPS-induced Cytokine Production

Vandenplas, Michel L.; Carlson, Russell W.; Jeyaretnam, Benjamin; McNeill, Brian; Barton, Michelle Henry; Norton, Natalie; Murray, Thomas F.; Moore, James N.

doi:10.1074/jbc.m205252200

Cited by 33 publications

(34 citation statements)

References 37 publications

(23 reference statements)

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“…Toll-like receptors have been identified in plants (38), where they also contribute to innate immunity. It is well documented that rhizobial and brucellae lipid-A molecules exhibit attenuated biological activity and very low endotoxicity compared with enterobacterial lipid-A molecules (39,40). This low level of activity of brucellae lipid A is thought to serve as a mechanism for immune evasion during the initial stages of host infection.…”

Section: Discussionmentioning

confidence: 99%

Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids

Ferguson

Datta

Baumgartner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

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Sinorhizobium meliloti, a legume symbiont, and Brucella abortus, a phylogenetically related mammalian pathogen, both require the bacterial-encoded BacA protein to establish chronic intracellular infections in their respective hosts. We found that the bacterial BacA proteins share sequence similarity with a family of eukaryotic peroxisomal-membrane proteins, including the human adrenoleukodystrophy protein, required for the efficient transport of verylong-chain fatty acids out of the cytoplasm. This insight, along with the increased sensitivity of BacA-deficient mutants to detergents and cell envelope-disrupting agents, led us to discover that BacA affects the very-long-chain fatty acid (27-OHC28:0 and 29-OHC30:0) content of both Sinorhizobium and Brucella lipid A. We discuss models for how BacA function affects the lipid-A fatty-acid content and why this activity could be important for the establishment of chronic intracellular infections. Sinorhizobia and brucellae are Gram-negative ␣-proteobacteria that live intracellularly within their respective hosts. Sinorhizobia form a beneficial symbiosis with agriculturally important legumes that results in the conversion of N 2 to NH 3 (1). In contrast, brucellae are highly infectious pathogens that cause abortions and infertility in domestic and wild mammals and a severe and debilitating zoonotic disease in humans (2). Brucella melitensis, Brucella suis, and Brucella abortus are potential biological warfare agents, and they are a serious concern because there is presently no human vaccine (3). Despite the strikingly different outcomes that sinorhizobia and brucellae eventually have on their hosts, commonalties exist in the chronicinfection process because both are endocytosed into host cells, where they adapt and survive for extensive periods of time within acidic, membrane-bound compartments (1, 2, 4, 5). More importantly, the close phylogenetic relatedness of the sinorhizobia and the brucellae that was revealed initially by RNA homology studies has been confirmed recently by determination of the complete genome sequences of Sinorhizobium meliloti, B. melitensis, and B. suis (6-8).The BacA protein, initially found to be essential for S. meliloti to form a long-term infection within alfalfa-plant cells (9), was also shown subsequently to be essential for the establishment and maintenance of chronic spleen and liver infections by B. abortus in BALB͞c mice (10). BacA is predicted to span the inner membrane of S. meliloti and B. abortus seven times, and it is homologous to the SbmA protein of Escherichia coli, a putative transporter of peptide antibiotics (9, 11). Although an S. meliloti bacA null mutant displays altered sensitivity to peptide antibiotics (11), the increased sensitivity of this mutant to detergents and cell envelope-disrupting agents supports an alternative model wherein the function of BacA affects the integrity of the bacterial cell envelope (12). Recently, an S. meliloti lpsB mutant, altered dramatically in its lipopolysaccharide (LPS) carbohydrate co...

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Section: Discussionmentioning

confidence: 99%

Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids

Ferguson

Datta

Baumgartner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

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“…17,18 Furthermore, another study showed that the biological properties of R. sin-1 LPS are species specific and most notably it was found that it can agonize mouse macrophages in a TLR2-dependent manner. 19,20 The lipid A of R. sin-1 LPS is structurally unusual lipid A differing in almost every aspect from those known to contribute to the toxicity of enteric LPS (Fig.…”

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

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LPS from Rhizobium sin-1 (R. sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R. sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R. sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferoninducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R. sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

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“…Recent findings have shown that nontoxic LIP A, such as that from Rh. capsulatus and Rhizobium Sin-1, act as antagonist of LPS [16,18].…”

Section: Discussionmentioning

confidence: 99%

“…The housekeeping gene GAPDH was used as an internal control. Five micrograms of total RNA was reverse-transcribed into cDNA using oligo(dT) [12][13][14][15][16][17][18] /mL/well (Mono Mac and fresh human monocytes) where they were allowed to adhere for 2 h. Thereafter, the cells were treated for 5 h with 0.1, 0.2 or 0.3 lg/mL of Hm LIP A alone or in combination with 0.01 lg/mL of E. coli LPS added 30 min after Hm LIP A. Thereafter, cell supernatants containing secreted TNF-a were harvested by centrifugation and stored at -80 C until analysis.…”

Section: Cell Culturementioning

confidence: 99%

“…sphaeroides [16,17]. More recently, it has been proven that Rhizobium Sin-1 LPS/ LIP A derivatives may act as antagonists of enteric LPS [18] in human cells. Hence, development of non-toxic LIP A structures that can act as antagonists for the toxic LIP A of enteric bacterial LPS may have important implications for the treatment of endotoxic shock [19].…”

Section: Introductionmentioning

confidence: 99%

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A novel lipid A from Halomonas magadiensis inhibits enteric LPS‐induced human monocyte activation

et al. 2006

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Lipopolysaccharide (LPS) endotoxin is the bacterial product responsible for the clinical syndrome of Gram‐negative septicemia and endotoxic shock. During sepsis, microbial antigens, such as LPS, activate monocytes and macrophages to produce several pro‐inflammatory cytokines, among which tumor necrosis factor‐α (TNF‐α) appears to be very important for the development of endotoxic shock. The endotoxic properties of LPS principally reside in the lipid A (LIP A) component, which is the primary immunostimulatory center of Gram‐negative bacteria. In recent years there has been a continuous effort to identify molecules able to antagonize the deleterious effects of endotoxic shock. In this study we show that a novel LIP A fraction from the LPS of Halomonas magadiensis (Hm), a Gram‐negative extremophilic and alkaliphilic bacterium, significantly inhibits the synthesis of TNF‐α by human monocytes activated by Escherichia coli LPS. LIP A from Hm exerts these effects by interfering with E. coli LPS for activation of Toll‐like receptor 4 expressed in human cells. This result defines Hm LIP A as a novel class of LPS antagonist whose structural features could be utilized for the design of compounds for the treatment of Gram‐negative sepsis.

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Rhizobium Sin-1 Lipopolysaccharide (LPS) Prevents Enteric LPS-induced Cytokine Production

Abstract: Endotoxin (lipopolysaccharide (LPS))

Cited by 33 publications

References 37 publications

Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids

Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

A novel lipid A from Halomonas magadiensis inhibits enteric LPS‐induced human monocyte activation

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