title: Rational design of adjuvants targeting the C-type lectin Mincle.
abstract: The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6'-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified atO-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model ofMycobacterium tuberculosisinfection. Here we describe the rational development of new molecules with powerful adjuvant properties.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.|Research Department, InvivoGen, F-31400 Toulouse, France.
authors.forename: Alexiane
authors.initials: A
authors.lastname: Decout
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.
authors.forename: Sandro
authors.initials: S
authors.lastname: Silva-Gomes
authors.affiliation: Research Department, InvivoGen, F-31400 Toulouse, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Drocourt
authors.affiliation: Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées (INSA), F-31077 Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Barbe
authors.affiliation: Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées (INSA), F-31077 Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Cueto
authors.affiliation: Research Department, InvivoGen, F-31400 Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lioux
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
authors.affiliation: Research Department, InvivoGen, F-31400 Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pérouzel
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vercellone
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Prandi
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Gilleron
authors.affiliation: Research Department, InvivoGen, F-31400 Toulouse, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Tiraby
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France; jerome.nigou@ipbs.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D002473:Cell Wall / Q000187:drug effects / Q000276:immunology; D003311:Cord Factors / Q000737:chemistry / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis / Q000187:drug effects; D009161:Mycobacterium / Q000276:immunology / Q000472:pathogenicity; D011971:Receptors, Immunologic / Q000737:chemistry / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; C482593:CLEC4D protein, human; D003311:Cord Factors; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D022223:Vaccines, Subunit
keywords: glycolipid; innate immunity; mycobacteria