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Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2675-2680. doi: 10.1073/pnas.1612421114. Epub 2017 Feb 21.

Rational design of adjuvants targeting the C-type lectin Mincle.

Author information

1
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France.
2
Research Department, InvivoGen, F-31400 Toulouse, France.
3
Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées (INSA), F-31077 Toulouse, France.
4
Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain.
5
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France; jerome.nigou@ipbs.fr.

Abstract

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 α-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.

KEYWORDS:

glycolipid; innate immunity; mycobacteria

PMID:
28223515
PMCID:
PMC5347620
DOI:
10.1073/pnas.1612421114
[Indexed for MEDLINE]
Free PMC Article

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