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

• Published in: Frontiers in cellular and infection microbiology 2013, Vol.3, p.3-3
• Main Authors: Maeshima, Nina, Fernandez, Rachel C
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - metabolism; Dimerization; Gram-Negative Bacteria - metabolism; Host Specificity; Humans; Immunity, Innate; innate immunity; Lipid A; Lipid A - chemistry; Lipid A - immunology; LPS; Lymphocyte Antigen 96 - immunology; Lymphocyte Antigen 96 - metabolism; Mice; Microbiology; Signal Transduction; signaling; TLR4; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2013.00003

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.