Trehalose dimycolate, an unusual glycolipid in the outer membrane of Mycobacterium tuberculosis, stimulates macrophages by binding to the macrophage receptor mincle. This stimulation plays an important role both in infection by mycobacteria and in the use of derivatives of mycobacteria as adjuvants to enhance the immune response. The mechanism of trehalose dimycolate binding to the C-type carbohydrate-recognition domain in human mincle has been investigated using a series of synthetic analogs of trehalose dimycolate and site-directed mutagenesis of the human protein. The results support a mechanism of binding acylated trehalose derivatives to human mincle that is very similar to the mechanism of binding to bovine mincle, in which one glucose residue in the trehalose headgroup of the glycolipid is ligated to the principle Ca(2+)-binding site in the carbohydrate-recognition domain, with specificity for the disaccharide resulting from interactions with the second glucose residue. Acyl chains attached to the 6-OH groups of trehalose enhance affinity, with the affinity dependent on the length of the acyl chains and the presence of a hydrophobic groove adjacent to the sugar-binding sites. The results indicate that the available crystal structure of the carbohydrate-recognition domain of human mincle is unlikely to be in a fully active conformation. Instead, the ligand-binding conformation probably resembles closely the structure observed for bovine mincle in complex with trehalose. These studies provide a basis for targeting human mincle as a means of inhibiting interactions with mycobacteria and as an approach to harnessing the ability of mincle to stimulate the immune response.
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http://dx.doi.org/10.1093/glycob/cwu072 | DOI Listing |
Mucosal Immunol
November 2024
Section of Immunology, Vetsuisse Faculty and Institute of Experimental Immunology, University of Zürich, 8057 Zurich, Switzerland; Medical Research Council Centre for Medical Mycology at the University of Exeter, Department of Biosciences, Faculty of Health and Life Sciences, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK. Electronic address:
The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity.
View Article and Find Full Text PDFNat Commun
October 2024
Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark.
Development of new vaccines tailored for difficult-to-target diseases is hampered by a lack of diverse adjuvants for human use, and none of the currently available adjuvants induce Th17 cells. Here, we develop a liposomal adjuvant, CAF®10b, that incorporates Mincle and Toll-like receptor 9 agonists. In parallel mouse and non-human primate studies comparing to CAF® adjuvants already in clinical trials, we report species-specific effects of adjuvant composition on the quality and magnitude of the responses.
View Article and Find Full Text PDFJ Phys Chem B
October 2024
Institut de Pharmacologie et de Biologie Structurale (IPBS), UMR5089, CNRS-Université de Toulouse III-Paul Sabatier, BP 64182, 31077 Toulouse, Cedex 4, France.
Glycobiology
December 2024
Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom.
Int J Mol Sci
September 2024
Department of Chemistry and Biochemistry, Center for Translational Medicine, University of Montana, Missoula, MT 59812, USA.
The Macrophage-Inducible C-type Lectin receptor (Mincle) plays a critical role in innate immune recognition and pathology, and therefore represents a promising target for vaccine adjuvants. Innovative trehalose-based Mincle agonists with improved pharmacology and potency may prove useful in the development of Th17-mediated adaptive immune responses. Herein, we report on in vitro and in silico investigations of specific Mincle ligand-receptor interactions required for the effective receptor engagement and activation of Th17-polarizing cytokines.
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