title: Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis.
abstract: The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-α) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.
authors.affiliation: Scientific Service Immunology, O.D. Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium.
authors.forename: Hermann Giresse
authors.initials: HG
authors.lastname: Tima
authors.forename: Juma''a Raheem
authors.initials: JR
authors.lastname: Al Dulayymi
authors.forename: Olivier
authors.initials: O
authors.lastname: Denis
authors.forename: Pauline
authors.initials: P
authors.lastname: Lehebel
authors.forename: Klarah Sherzad
authors.initials: KS
authors.lastname: Baols
authors.forename: Mohsin Omar
authors.initials: MO
authors.lastname: Mohammed
authors.forename: Laurent
authors.initials: L
authors.lastname: L'Homme
authors.forename: Mohaned Mohammed
authors.initials: MM
authors.lastname: Sahb
authors.forename: Georges
authors.initials: G
authors.lastname: Potemberg
authors.forename: Sylvie
authors.initials: S
authors.lastname: Legrand
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Mark Stephen
authors.initials: MS
authors.lastname: Baird
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Marta
authors.initials: M
authors.lastname: Romano
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002454:Cell Differentiation; D002473:Cell Wall / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D004952:Esters / Q000737:chemistry; D005947:Glucose; D006017:Glycolipids / Q000138:chemical synthesis / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009171:Mycolic Acids / Q000737:chemistry*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014199:Trehalose / Q000737:chemistry / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C113583:Clecsf8 protein, mouse; D004952:Esters; D006017:Glycolipids; D058847:Inflammasomes; D015850:Interleukin-6; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009171:Mycolic Acids; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014199:Trehalose; D005947:Glucose