title: Recognition of lipid A variants by the TLR4-MD-2 receptor complex.
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.
authors: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors: Nina
authors: N
authors: Maeshima
authors: Rachel C
authors: RC
authors: Fernandez
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D006090:Gram-Negative Bacteria / Q000378:metabolism; D058507:Host Specificity; D006801:Humans; D007113:Immunity, Innate; D008050:Lipid A / Q000737:chemistry / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; C495377:LY96 protein, human; D008050:Lipid A; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: LPS; TLR4; innate immunity; lipid A; signaling