Rational design of adjuvants targeting the C-type lectin Mincle

被引:91
作者
Decout, Alexiane [1 ,2 ,5 ]
Silva-Gomes, Sandro [1 ]
Drocourt, Daniel [2 ]
Barbe, Sophie [3 ]
Andre, Isabelle [3 ]
Cueto, Francisco [4 ]
Lioux, Thierry [2 ]
Sancho, David [4 ]
Perouzel, Eric [2 ]
Vercellone, Alain [1 ]
Prandi, Jacques [1 ]
Gilleron, Martine [1 ]
Tiraby, Gerard [2 ]
Nigou, Jerome [1 ]
机构
[1] Univ Paul Sabatier, Univ Toulouse, CNRS, Inst Pharmacol & Biol Struct, F-31077 Toulouse, France
[2] InvivoGen, Dept Res, F-31400 Toulouse, France
[3] Univ Toulouse, INSA, INRA, CNRS,Lab Ingn Syst Biol & Proc, F-31077 Toulouse, France
[4] Ctr Nacl Invest Cardiovasc Carlos III, Madrid 28029, Spain
[5] GLYcoDiag, Res Dept, F-45067 Orleans 2, France
关键词
mycobacteria; glycolipid; innate immunity; ACID-CONTAINING GLYCOLIPIDS; CORD FACTOR; MYCOBACTERIUM-TUBERCULOSIS; TREHALOSE DIMYCOLATE; RECOGNITION; RECEPTOR; RESPONSES; DIESTERS; CELLS;
D O I
10.1073/pnas.1612421114
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 at O-6 by a synthetic alpha-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 of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties.
引用
收藏
页码:2675 / 2680
页数:6
相关论文
共 34 条
[1]   Freund's adjuvant, NOD2 and mycobacteria [J].
Behr, Marcel A. ;
Divangahi, Maziar .
CURRENT OPINION IN MICROBIOLOGY, 2015, 23 :126-132
[3]   THE ENVELOPE OF MYCOBACTERIA [J].
BRENNAN, PJ ;
NIKAIDO, H .
ANNUAL REVIEW OF BIOCHEMISTRY, 1995, 64 :29-63
[4]   Characterization of cationic liposomes based on dimethyldioctadecylammonium and synthetic cord factor from M. tuberculosis (trehalose 6,6′-dibehenate) -: A novel adjuvant inducing both strong CMI and antibody responses [J].
Davidsen, J ;
Rosenkrands, I ;
Christensen, D ;
Vangala, A ;
Kirby, D ;
Perrie, Y ;
Agger, EM ;
Andersen, P .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2005, 1718 (1-2) :22-31
[5]   Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle [J].
Feinberg, Hadar ;
Rambaruth, Neela D. S. ;
Jegouzo, Sabine A. F. ;
Jacobsen, Kristian M. ;
Djurhuus, Rasmus ;
Poulsen, Thomas B. ;
Weis, William I. ;
Taylor, Maureen E. ;
Drickamer, Kurt .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (40) :21222-+
[6]   Mechanism for Recognition of an Unusual Mycobacterial Glycolipid by the Macrophage Receptor Mincle [J].
Feinberg, Hadar ;
Jegouzo, Sabine A. F. ;
Rowntree, Thomas J. W. ;
Guan, Yue ;
Brash, Matthew A. ;
Taylor, Maureen E. ;
Weis, William I. ;
Drickamer, Kurt .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (40) :28457-28465
[7]   Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL [J].
Furukawa, Atsushi ;
Kamishikiryo, Jun ;
Mori, Daiki ;
Toyonaga, Kenji ;
Okabe, Yuki ;
Toji, Aya ;
Kanda, Ryo ;
Miyake, Yasunobu ;
Ose, Toyoyuki ;
Yamasaki, Sho ;
Maenaka, Katsumi .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (43) :17438-17443
[8]   Glycerol Monomycolate Is a Novel Ligand for the Human, but Not Mouse Macrophage Inducible C-type Lectin, Mincle [J].
Hattori, Yuki ;
Morita, Daisuke ;
Fujiwara, Nagatoshi ;
Mori, Daiki ;
Nakamura, Takashi ;
Harashima, Hideyoshi ;
Yamasaki, Sho ;
Sugita, Masahiko .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (22) :15405-15412
[9]   Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle [J].
Ishikawa, Eri ;
Ishikawa, Tetsuaki ;
Morita, Yasu S. ;
Toyonaga, Kenji ;
Yamada, Hisakata ;
Takeuchi, Osamu ;
Kinoshita, Taroh ;
Akira, Shizuo ;
Yoshikai, Yasunobu ;
Yamasaki, Sho .
JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (13) :2879-2888
[10]   Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate [J].
Jegouzo, Sabine A. F. ;
Harding, Edward C. ;
Acton, Oliver ;
Rex, Maximus J. ;
Fadden, Andrew J. ;
Taylor, Maureen E. ;
Drickamer, Kurt .
GLYCOBIOLOGY, 2014, 24 (12) :1291-1300