title: Modulating the innate immune response by combinatorial engineering of endotoxin.
abstract: Despite its highly inflammatory nature, LPS is a molecule with remarkable therapeutic potential. Lipid A is a glycolipid that serves as the hydrophobic anchor of LPS and constitutes a potent ligand of the Toll-like receptor (TLR)4/myeloid differentiation factor 2 receptor of the innate immune system. A less toxic mixture of monophosphorylated lipid A species (MPL) recently became the first new Food and Drug Administration-approved adjuvant in over 70 y. Whereas wild-type Escherichia coli LPS provokes strong inflammatory MyD88 (myeloid differentiation primary response gene 88)-mediated TLR4 signaling, MPL preferentially induces less inflammatory TRIF (TIR-domain-containing adaptor-inducing IFN-β)-mediated responses. Here, we developed a system for combinatorial structural diversification of E. coli lipid A, yielding a spectrum of bioactive variants that display distinct TLR4 agonist activities and cytokine induction. Mice immunized with engineered lipid A/antigen emulsions exhibited robust IgG titers, indicating the efficacy of these molecules as adjuvants. This approach demonstrates how combinatorial engineering of lipid A can be exploited to generate a spectrum of immunostimulatory molecules for vaccine and therapeutics development.
authors.affiliation: Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Brittany D
authors.initials: BD
authors.lastname: Needham
authors.forename: Sean M
authors.initials: SM
authors.lastname: Carroll
authors.forename: David K
authors.initials: DK
authors.lastname: Giles
authors.forename: George
authors.initials: G
authors.lastname: Georgiou
authors.forename: Marvin
authors.initials: M
authors.lastname: Whiteley
authors.forename: M Stephen
authors.initials: MS
authors.lastname: Trent
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001483:Base Sequence; D020650:Combinatorial Chemistry Techniques; D016207:Cytokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015723:Gene Library; D005798:Genes, Bacterial; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008050:Lipid A / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009000:Monocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4