Recognition of lipid A variants by the TLR4-MD-2 receptor complex

Maeshima, Nina; Fernandez, Rachel C.

doi:10.3389/fcimb.2013.00003

Cited by 192 publications

(168 citation statements)

References 115 publications

(159 reference statements)

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“…It has been hypothesized that modification of lipid A in response to different host microenvironments helps pathogens to survive in the hostile host by camouflaging the pathogen from host immune detection, promoting antimicrobial peptide resistance and by altering outer membrane properties (3,10,11). However, direct evidence showing that bacteria remodel their lipid A in vivo is lacking.…”

mentioning

confidence: 99%

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Llobet

Martínez-Moliner

Moranta

et al. 2015

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

134

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The outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacyl-modified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrug-resistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO-dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.

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mentioning

confidence: 99%

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Llobet

Martínez-Moliner

Moranta

et al. 2015

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

134

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“…The signaling events following TLR4 activation involve two pathways, the MyD88-dependent pathway, which leads to the expression of pro-inflammatory gene products, and the TRIF-dependent pathway, leading to the expression of interferon-␤ and type I interferon-inducible genes (1). Many variations in the basic structure of lipid A exist, and they can influence the strength and nature of the evoked inflammatory response (2,3). Such structure-function relationships are important determinants for the outcome of Gram-negative bacterial infections.…”

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confidence: 99%

Lipopolysaccharide Engineering in Neisseria meningitidis

Pupo

Hamstra

Meiring

et al. 2014

Journal of Biological Chemistry

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“…3. Observed differences resulted in the lack of one or two FAs or phosphate substitutions compared with published data; this was expected to induce differences in the MD-2/TLR4 activation and in cytokine production (2).…”

Section: Discussionmentioning

confidence: 94%

Structural and biological characteristics of different forms of V. filiformis lipid A: use of MS to highlight structural discrepancies

Breton

Новиков

Martin

et al. 2017

Journal of Lipid Research

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bacterium. This is a signature for which each small detail may exert important differences on LPS recognition by host cells and signal transduction (2). LPS does not necessarily induce a toxic response, so all LPSs are not endotoxins, but endotoxins are always composed of LPSs. LPSs are the first nonsecreted toxins found to interact with host innate immunity, generating cytokine production, immune cell recruitment, and specific host-cell responses leading, at higher doses, to multiple organ failure and septic shock (3). The smallest change in the structures of LPSs or their hydrophobic moiety, named lipid A, is directly linked to innate immune recognition and development of a specific host response. The interaction between LPS molecules and their innate receptor, the MD-2/TLR4 complex, is greatly affected by the fine details of LPS structures. First, LPS molecules are recognized by the LPS binding protein and presented as monomers to the soluble or membrane CD14 receptors. Then, the LPS is transferred to the MD-2/TLR4 complex (2, 4) allowing its dimerization of the receptor through ionic and hydrophobic interactions and activation of the cellular signaling pathways. Among these, the activation of the NFB pathway directly induces rapid pro-inflammatory cytokine production. Secreted cytokines are ultimately central to the generation of efficient responses to pathogens and the activation of the adaptive immune system (5, 6).The Neisseriaceae family members, including the Vitreoscilla genus, are obligate aerobic bacteria described for the first time in 1949 by E. G. Pringsheim (7) as colorless gliding filamentous organisms. Similar organisms were in fact described earlier by Cohn (8) in 1870. They are known as the first genus in which bacterial hemoglobin (VHb) was discovered (9).Abstract Vitreoscilla filiformis is a Gram-negative bacterium isolated from spa waters and described for its beneficial effects on the skin. We characterized the detailed structure of its lipopolysaccharide (LPS) lipid A moiety, an active component of the bacterium that contributes to the observed skin activation properties. Two different batches differing in postculture cell recovery were tested. Chemical analyses and mass spectra, obtained before and after mild-alkali treatments, revealed that these lipids A share the common bisphosphorylated - (1→6) Lipopolysaccharides (LPSs) are the main components of the outer-membrane of Gram-negative bacteria, representing about 10 6 molecules per bacterium (1). They are also major antigens displaying unique structures for each

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Recognition of lipid A variants by the TLR4-MD-2 receptor complex

Cited by 192 publications

References 115 publications

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Lipopolysaccharide Engineering in Neisseria meningitidis

Structural and biological characteristics of different forms of V. filiformis lipid A: use of MS to highlight structural discrepancies

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