title: Mycobacterium tuberculosis-associated synthetic mycolates differentially exert immune stimulatory adjuvant activity.
abstract: Mycolic acids (MAs) are highly hydrophobic long-chain α-alkyl β-hydroxy fatty acids present in the cell wall of Mycobacterium tuberculosis (Mtb) as a complex mixture of molecules with a common general structure but with variable functional groups in the meromycolate chain. In this study, we addressed the relationship between the MA molecular structure and their contribution to the development of T-cell immune responses. Hereto, we used the model antigen ovalbumin and single synthetic MAs, differing in oxygenation class and cis versus trans proximal cyclopropane configuration, as immune stimulatory agents. Subcutaneous delivery of liposome-formulated MAs with a proximal cis cyclopropane elicited antigen-specific Th1 and cytotoxic T-cell immune responses, whereas intratracheal immunization elicited pulmonary Th17 responses. These immune stimulatory activities depended not only on the cis versus trans proximal cyclopropane configuration but also on the MA oxygenation class. Our study thus shows that both the presence and nature of the functional groups in the meromycolate chain affect the immune stimulatory adjuvant activity of Mtb mycolates and suggests that Mtb bacilli may impact on the host protective immune response by modulating the cis versus trans stereochemistry of its mycolates as well as by altering the oxygenation class of the meromycolate functional group.
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Smet
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pollard
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Ans
authors.initials: A
authors.lastname: De Beuckelaer
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Medical Biotechnology Center, Flanders Institute for Biotechnology, Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van Hoecke
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Seppe
authors.initials: S
authors.lastname: Vander Beken
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
authors.affiliation: School of Chemistry, Bangor University, Bangor, United Kingdom.
authors.forename: Juma'a R
authors.initials: JR
authors.lastname: Al Dulayymi
authors.affiliation: Immunology Department, Scientific Institute of Public Health, Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.affiliation: Department of Biochemistry, University of Pretoria, Pretoria, South Africa.
authors.forename: Jan
authors.initials: J
authors.lastname: Verschoor
authors.affiliation: School of Chemistry, Bangor University, Bangor, United Kingdom.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Baird
authors.affiliation: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Johan.Grooten@ugent.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007155:Immunologic Factors; D056747:Immunomodulation; D000069555:Injection, Intratympanic; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D008081:Liposomes / Q000737:chemistry; D008213:Lymphocyte Activation; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism; D009171:Mycolic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D010713:Phosphatidylcholines / Q000737:chemistry; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008081:Liposomes; D009171:Mycolic Acids; D010713:Phosphatidylcholines; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma
keywords: Adjuvant biolipids; Mycobacterium tuberculosis; Mycolic acid; T-cell responses