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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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Related in: MedlinePlus

Simplified diagram of signaling by LPS on host cells. LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum, passed to CD14, then transferred to MD-2 and TLR4, which form a complex on the cell surface. LPS-induced receptor dimerization is followed by recruitment of the adaptor proteins TIRAP and MyD88, which promotes activation of the transcription factor NFκB. The TLR4-MD-2 complex can also be internalized, which recruits a different set of adaptor proteins, TRIF and TRAM, promoting activation of IRF3 and production of type I interferons, as well as delayed activation of NFκB.
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Figure 2: Simplified diagram of signaling by LPS on host cells. LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum, passed to CD14, then transferred to MD-2 and TLR4, which form a complex on the cell surface. LPS-induced receptor dimerization is followed by recruitment of the adaptor proteins TIRAP and MyD88, which promotes activation of the transcription factor NFκB. The TLR4-MD-2 complex can also be internalized, which recruits a different set of adaptor proteins, TRIF and TRAM, promoting activation of IRF3 and production of type I interferons, as well as delayed activation of NFκB.

Mentions: LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum. LBP then transfers LPS to CD14, which can be found either in soluble form or linked to the cell surface by a glycosyl-phosphatidylinositol (GPI) anchor. CD14 presents LPS to the TLR4 and MD-2 (TLR4-MD-2) receptor complex. Upon binding LPS, the TLR4-MD-2 heterodimer is thought to dimerize, which brings together their intracellular TIR domains and creates a scaffold for the recruitment of adaptor proteins [reviewed in (Lu et al., 2008) and summarized in Figure 2].


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

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

Simplified diagram of signaling by LPS on host cells. LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum, passed to CD14, then transferred to MD-2 and TLR4, which form a complex on the cell surface. LPS-induced receptor dimerization is followed by recruitment of the adaptor proteins TIRAP and MyD88, which promotes activation of the transcription factor NFκB. The TLR4-MD-2 complex can also be internalized, which recruits a different set of adaptor proteins, TRIF and TRAM, promoting activation of IRF3 and production of type I interferons, as well as delayed activation of NFκB.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Simplified diagram of signaling by LPS on host cells. LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum, passed to CD14, then transferred to MD-2 and TLR4, which form a complex on the cell surface. LPS-induced receptor dimerization is followed by recruitment of the adaptor proteins TIRAP and MyD88, which promotes activation of the transcription factor NFκB. The TLR4-MD-2 complex can also be internalized, which recruits a different set of adaptor proteins, TRIF and TRAM, promoting activation of IRF3 and production of type I interferons, as well as delayed activation of NFκB.
Mentions: LPS is extracted from bacterial membranes by LPS binding protein (LBP) in serum. LBP then transfers LPS to CD14, which can be found either in soluble form or linked to the cell surface by a glycosyl-phosphatidylinositol (GPI) anchor. CD14 presents LPS to the TLR4 and MD-2 (TLR4-MD-2) receptor complex. Upon binding LPS, the TLR4-MD-2 heterodimer is thought to dimerize, which brings together their intracellular TIR domains and creates a scaffold for the recruitment of adaptor proteins [reviewed in (Lu et al., 2008) and summarized in Figure 2].

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