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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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Chemical structure of lipid A molecules. (A) Hexa-acylated lipid A from E. coli. Red numbers indicate carbon numbering. (B) Hexa-acylated lipid A from Y. pestis grown at 27°C. (C) Tetra-acylated lipid A from Y. pestis grown at 37°C. (D) Tetra-acylated lipid IVA, a biosynthetic precursor of hexa-acylated lipid A. (E) The synthetic molecule Eritoran. (F) Monophosphoryl lipid A (MPLA). (G) Glucosamine-modified lipid A from B. pertussis (strain BP338, a Tohama I derivative).
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Figure 3: Chemical structure of lipid A molecules. (A) Hexa-acylated lipid A from E. coli. Red numbers indicate carbon numbering. (B) Hexa-acylated lipid A from Y. pestis grown at 27°C. (C) Tetra-acylated lipid A from Y. pestis grown at 37°C. (D) Tetra-acylated lipid IVA, a biosynthetic precursor of hexa-acylated lipid A. (E) The synthetic molecule Eritoran. (F) Monophosphoryl lipid A (MPLA). (G) Glucosamine-modified lipid A from B. pertussis (strain BP338, a Tohama I derivative).

Mentions: Most of what is known about how lipid A in LPS is recognized by the TLR4-MD-2 complex on animal cells has been studied using hexa-acylated lipid A from Escherichia coli, which is a strong agonist of TLR4 signaling. E. coli lipid A (Figure 3A) consists of a di-glucosamine backbone, 1- and 4′-phosphate groups, and six fatty acyl chains, of which four are directly linked to the glucosamine head group at positions 2, 3, 2′ and 3′, and two are secondary chains attached to the hydroxyl groups of the 2′- and 3′-linked chains (R2″ and R3″, respectively). E. coli lipid A is synthesized in a series of reactions catalyzed by genes in the Raetz pathway. The first step is the acylation of UDP-N-acetylglucosamine (UDP-GlcNAc) at the C-3 position by LpxA. Next, LpxC catalyzes the deacetylation at C-2, followed by acylation of the C-2 amide by LpxD to yield UDP-2,3-diacylglucosamine. This is cleaved by the pyrophosphatase LpxH to release UMP and generate lipid X. Lipid X is then condensed with a second molecule of UDP-2-3-diacylglucosamine by LpxB, forming a disaccharide, diglucosamine-1-phosphate. LpxK then adds a phosphate group at the C-4′ position to yield lipid IVA. A Kdo sugar group is added at C-6′ by KdtA (or WaaA) and the final steps of lipid A biosynthesis involve the addition of lauroyl and myristoyl groups by LpxL and LpxM at positions C-2′ and C-3′, respectively, to yield lipid A [reviewed in (Raetz and Whitfield, 2002)].


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

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

Chemical structure of lipid A molecules. (A) Hexa-acylated lipid A from E. coli. Red numbers indicate carbon numbering. (B) Hexa-acylated lipid A from Y. pestis grown at 27°C. (C) Tetra-acylated lipid A from Y. pestis grown at 37°C. (D) Tetra-acylated lipid IVA, a biosynthetic precursor of hexa-acylated lipid A. (E) The synthetic molecule Eritoran. (F) Monophosphoryl lipid A (MPLA). (G) Glucosamine-modified lipid A from B. pertussis (strain BP338, a Tohama I derivative).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569842&req=5

Figure 3: Chemical structure of lipid A molecules. (A) Hexa-acylated lipid A from E. coli. Red numbers indicate carbon numbering. (B) Hexa-acylated lipid A from Y. pestis grown at 27°C. (C) Tetra-acylated lipid A from Y. pestis grown at 37°C. (D) Tetra-acylated lipid IVA, a biosynthetic precursor of hexa-acylated lipid A. (E) The synthetic molecule Eritoran. (F) Monophosphoryl lipid A (MPLA). (G) Glucosamine-modified lipid A from B. pertussis (strain BP338, a Tohama I derivative).
Mentions: Most of what is known about how lipid A in LPS is recognized by the TLR4-MD-2 complex on animal cells has been studied using hexa-acylated lipid A from Escherichia coli, which is a strong agonist of TLR4 signaling. E. coli lipid A (Figure 3A) consists of a di-glucosamine backbone, 1- and 4′-phosphate groups, and six fatty acyl chains, of which four are directly linked to the glucosamine head group at positions 2, 3, 2′ and 3′, and two are secondary chains attached to the hydroxyl groups of the 2′- and 3′-linked chains (R2″ and R3″, respectively). E. coli lipid A is synthesized in a series of reactions catalyzed by genes in the Raetz pathway. The first step is the acylation of UDP-N-acetylglucosamine (UDP-GlcNAc) at the C-3 position by LpxA. Next, LpxC catalyzes the deacetylation at C-2, followed by acylation of the C-2 amide by LpxD to yield UDP-2,3-diacylglucosamine. This is cleaved by the pyrophosphatase LpxH to release UMP and generate lipid X. Lipid X is then condensed with a second molecule of UDP-2-3-diacylglucosamine by LpxB, forming a disaccharide, diglucosamine-1-phosphate. LpxK then adds a phosphate group at the C-4′ position to yield lipid IVA. A Kdo sugar group is added at C-6′ by KdtA (or WaaA) and the final steps of lipid A biosynthesis involve the addition of lauroyl and myristoyl groups by LpxL and LpxM at positions C-2′ and C-3′, respectively, to yield lipid A [reviewed in (Raetz and Whitfield, 2002)].

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
Related in: MedlinePlus