title: A simple mycobacterial monomycolated glycerol lipid has potent immunostimulatory activity.
abstract: It is a long held belief that the strong immunostimulatory activity of the Mycobacterium bovis bacillus Calmette-Guérin vaccine and Freund's complete adjuvant is due to specific mycobacterial cell envelope components, such as lipids and polysaccharides. Implicated mycobacterial lipids include, among others, the so-called cord factor or trehalose dimycolate, but limited information is available regarding the precise molecular nature of the stimulatory components responsible for the interaction with human APCs. In this regard, the majority of research aimed at identifying and characterizing individual immunostimulatory mycobacterial lipids has been performed in the murine system using bone marrow-derived dendritic cells. In this study, it is documented that potent immunostimulatory activity lies within the bacillus Calmette-Guérin nonpolar lipid class. This activity can be narrowed down to a remarkably simple monomycolyl glycerol (MMG) with the ability to stimulate human dendritic cells as assessed by enhanced expression of activation markers and the release of proinflammatory cytokines. A synthetic analog of MMG based on 32 carbons (C(32)) was found to exhibit comparable levels of immunostimulatory activities. Immunization of mice with the tuberculosis vaccine candidate, Ag85B-ESAT-6, in MMG or the synthetic analog using cationic liposomes as the delivery vehicle was found to give rise to a prominent Th1 response characterized by significant levels of IFN-gamma. Together, this development opens up the possibility of producing a novel class of chemically defined lipid adjuvants to enhance the activity of new vaccine formulations, directed against infectious agents including tuberculosis.
authors.affiliation: Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Andersen
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Gomes
authors.forename: Veemal
authors.initials: V
authors.lastname: Bhowruth
authors.forename: Kevin J C
authors.initials: KJ
authors.lastname: Gibson
authors.forename: Rune V
authors.initials: RV
authors.lastname: Petersen
authors.forename: David E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D003311:Cord Factors / Q000008:administration & dosage / Q000276:immunology; D003353:Corynebacterium diphtheriae / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005990:Glycerol / Q000276:immunology*; D006017:Glycolipids / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000737:chemistry / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009171:Mycolic Acids / Q000008:administration & dosage / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D003311:Cord Factors; D006017:Glycolipids; D009171:Mycolic Acids; C016319:corynomycoloyl-D-trehalose; C013898:corynomycolic acid; D005990:Glycerol