title: The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4.
abstract: The inflammatory toxicity of lipopolysaccharide (LPS), a component of bacterial cell walls, is driven by the adaptor proteins myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta (TRIF), which together mediate signaling by the endotoxin receptor Toll-like receptor 4 (TLR4). Monophosphoryl lipid A (MPLA) is a low-toxicity derivative of LPS with useful immunostimulatory properties, which is nearing regulatory approval for use as a human vaccine adjuvant. We report here that, in mice, the low toxicity of MPLA's adjuvant function is associated with a bias toward TRIF signaling, which we suggest is likely caused by the active suppression, rather than passive loss, of proinflammatory activity of this LPS derivative. This finding may have important implications for the development of future vaccine adjuvants.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, 570 South Preston Street, Louisville, KY 40202, USA.
authors.forename: Verónica
authors.initials: V
authors.lastname: Mata-Haro
authors.forename: Caglar
authors.initials: C
authors.lastname: Cekic
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Casella
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mitchell
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity; D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D007114:Immunization; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000633:toxicity; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D016207:Cytokines; D008050:Lipid A; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C048436:monophosphoryl lipid A