Schematic of the basic structure of lipopolysaccharide.

Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Maeshima N, Fernandez RC - Front Cell Infect Microbiol (2013) Bottom Line: LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response.Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response.Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. View Article: PubMed Central - PubMed Affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. ABSTRACT Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response. Most of what is known about how LPS is recognized by the TLR4-MD-2 receptor complex on animal cells has been studied using Escherichia coli lipid A, which is a strong agonist of TLR4 signaling. Recent work from several groups, including our own, has shown that several important pathogenic bacteria can modify their LPS or lipid A molecules in ways that significantly alter TLR4 signaling to NFκB. Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response. Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. In this review, we provide an overview of lipid A variants from several human pathogens, how the basic structure of lipid A is recognized by mouse and human TLR4-MD-2 receptor complexes, as well as how alteration of this pattern affects its recognition by TLR4 and impacts the downstream immune response. Show MeSH Major Lipid A/chemistry/immunology* Lymphocyte Antigen 96/immunology/metabolism* Toll-Like Receptor 4/immunology/metabolism* Minor Animals Cytokines/metabolism Dimerization Gram-Negative Bacteria/metabolism Host Specificity Humans Immunity, Innate Mice Signal Transduction Related in: MedlinePlus	© Copyright Policy - open-access Related In: Results - Collection License Show All Figures getmorefigures.php?uid=PMC3569842&req=5 Figure 1: Schematic of the basic structure of lipopolysaccharide. LPS consists of three regions: from the bottom, lipid A (chair structure indicates di-glucosamine headgroup, red circles indicate phosphate groups, squiggly lines indicate acyl chains), core sugars, and O-antigen, which consists of repeating units (denoted in brackets, with an “n”) of oligosaccharides. Mentions: Lipopolysaccharide (LPS) is a well-characterized PAMP found in the outer leaflet of the outer membrane of most Gram-negative bacteria. It has three regions (Figure 1), a lipid A molecule (endotoxin), which anchors LPS in the outer membrane, a core sugar consisting of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) moieties, and the O antigen, which consists of repeating oligosaccharide units (Raetz and Whitfield, 2002). The lipid A component of LPS is recognized by Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on host cells (Kawai and Akira, 2010).

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

Maeshima N, Fernandez RC - Front Cell Infect Microbiol (2013)

Bottom Line: LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response.Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response.Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.

ABSTRACT

Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response. Most of what is known about how LPS is recognized by the TLR4-MD-2 receptor complex on animal cells has been studied using Escherichia coli lipid A, which is a strong agonist of TLR4 signaling. Recent work from several groups, including our own, has shown that several important pathogenic bacteria can modify their LPS or lipid A molecules in ways that significantly alter TLR4 signaling to NFκB. Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response. Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. In this review, we provide an overview of lipid A variants from several human pathogens, how the basic structure of lipid A is recognized by mouse and human TLR4-MD-2 receptor complexes, as well as how alteration of this pattern affects its recognition by TLR4 and impacts the downstream immune response.

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Related in: MedlinePlus

Schematic of the basic structure of lipopolysaccharide. LPS consists of three regions: from the bottom, lipid A (chair structure indicates di-glucosamine headgroup, red circles indicate phosphate groups, squiggly lines indicate acyl chains), core sugars, and O-antigen, which consists of repeating units (denoted in brackets, with an “n”) of oligosaccharides.

Related In: Results - Collection

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Figure 1: Schematic of the basic structure of lipopolysaccharide. LPS consists of three regions: from the bottom, lipid A (chair structure indicates di-glucosamine headgroup, red circles indicate phosphate groups, squiggly lines indicate acyl chains), core sugars, and O-antigen, which consists of repeating units (denoted in brackets, with an “n”) of oligosaccharides.

Mentions: Lipopolysaccharide (LPS) is a well-characterized PAMP found in the outer leaflet of the outer membrane of most Gram-negative bacteria. It has three regions (Figure 1), a lipid A molecule (endotoxin), which anchors LPS in the outer membrane, a core sugar consisting of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) moieties, and the O antigen, which consists of repeating oligosaccharide units (Raetz and Whitfield, 2002). The lipid A component of LPS is recognized by Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on host cells (Kawai and Akira, 2010).