The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Jeanyves Dube - One of the best experts on this subject based on the ideXlab platform.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns partially complete Freund’s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel BehrAbstract:Complete Freund's adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMps) to study mycobacterial immunity and immunopathogenesis.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns work synergistically to recapitulate complete Freund\'s adjuvant
2019Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Abstract Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to induce experimental autoimmunity qualitatively similar to the whole mycobacteria in CFA. This research outlines how to replace CFA with a consistent, molecularly defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
Kurt Drickamer - One of the best experts on this subject based on the ideXlab platform.
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binding sites for acylated Trehalose analogs of glycolipid ligands on an extended carbohydrate recognition domain of the macrophage receptor mincle
Journal of Biological Chemistry, 2016Co-Authors: H Feinberg, Sabine A. F. Jégouzo, Maureen E. Taylor, N D S Rambaruth, Kristian M Jacobsen, Rasmus Djurhuus, Thomas B Poulsen, William I Weis, Kurt DrickamerAbstract:Abstract The macrophage receptor mincle binds to Trehalose Dimycolate on the surface of Mycobacterium tuberculosis. Signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. In previous work the mechanism for binding of the sugar headgroup of Trehalose Dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are attached to the 6-hydroxyl groups, has been the subject of speculation. In the work reported here, the interaction of Trehalose derivatives with bovine mincle has been probed with a series of synthetic mimics of Trehalose Dimycolate in binding assays, in structural studies by x-ray crystallography, and by site-directed mutagenesis. Binding studies reveal that, rather than reflecting specific structural preference, the apparent affinity of mincle for ligands with hydrophobic substituents correlates with their overall size. Structural and mutagenesis analysis provides evidence for interaction of the hydrophobic substituents with multiple different portions of the surface of mincle and confirms the presence of three Ca2+-binding sites. The structure of an extended portion of the extracellular domain of mincle, beyond the minimal C-type carbohydrate recognition domain, also constrains the way the binding domains may interact on the surface of macrophages.
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Mouse mincle: characterization as a model for human mincle and evolutionary implications.
Molecules (Basel Switzerland), 2015Co-Authors: Neela D. S. Rambaruth, Sabine A. F. Jégouzo, Maureen E. Taylor, Hayley Marlor, Kurt DrickamerAbstract:Mincle, the macrophage-inducible C-type lectin also known as CLEC-4E, binds to the mycobacterial glycolipid Trehalose Dimycolate and initiates a signaling cascade by serving as a receptor for Mycobacterium tuberculosis and other pathogenic mycobacterial species. Studies of the biological functions of human mincle often rely on mouse models, based on the assumption that the biological properties of the mouse receptor mimic those of the human protein. Experimental support for this assumption has been obtained by expression of the carbohydrate-recognition domain of mouse mincle and characterization of its interaction with small molecule analogs of Trehalose Dimycolate. The results confirm that the ligand-binding properties of mouse mincle closely parallel those of the human receptor. These findings are consistent with the conservation of key amino acid residues that have been shown to form the ligand-binding site in human and cow mincle. Sequence alignment reveals that these residues are conserved in a wide range of mammalian species, suggesting that mincle has a conserved function in binding ligands that may include endogenous mammalian glycans or pathogen glycans in addition to Trehalose Dimycolate.
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Defining the conformation of human mincle that interacts with mycobacterial Trehalose Dimycolate
Glycobiology, 2014Co-Authors: Sabine A. F. Jégouzo, Edward C. Harding, Oliver Acton, Maximus J. Rex, Andrew J. Fadden, Maureen E. Taylor, Kurt DrickamerAbstract: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 Ca2+-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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mechanism for recognition of an unusual mycobacterial glycolipid by the macrophage receptor mincle
Journal of Biological Chemistry, 2013Co-Authors: H Feinberg, Sabine A. F. Jégouzo, Maureen E. Taylor, William I Weis, Thomas J W Rowntree, Yue Guan, Matthew A Brash, Kurt DrickamerAbstract:Binding of the macrophage lectin mincle to Trehalose Dimycolate, a key glycolipid virulence factor on the surface of Mycobacterium tuberculosis and Mycobacterium bovis, initiates responses that can lead both to toxicity and to protection of these pathogens from destruction. Crystallographic structural analysis, site-directed mutagenesis, and binding studies with glycolipid mimics have been used to define an extended binding site in the C-type carbohydrate recognition domain (CRD) of bovine mincle that encompasses both the headgroup and a portion of the attached acyl chains. One glucose residue of the Trehalose Glcα1–1Glcα headgroup is liganded to a Ca2+ in a manner common to many C-type CRDs, whereas the second glucose residue is accommodated in a novel secondary binding site. The additional contacts in the secondary site lead to a 36-fold higher affinity for Trehalose compared with glucose. An adjacent hydrophobic groove, not seen in other C-type CRDs, provides a docking site for one of the acyl chains attached to the Trehalose, which can be targeted with small molecule analogs of Trehalose Dimycolate that bind with 52-fold higher affinity than Trehalose. The data demonstrate how mincle bridges between the surfaces of the macrophage and the mycobacterium and suggest the possibility of disrupting this interaction. In addition, the results may provide a basis for design of adjuvants that mimic the ability of mycobacteria to stimulate a response to immunization that can be employed in vaccine development.
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Mechanism for Recognition of an Unusual Mycobacterial Glycolipid by the Macrophage Receptor Mincle.
The Journal of biological chemistry, 2013Co-Authors: Hadar Feinberg, Sabine A. F. Jégouzo, Maureen E. Taylor, William I Weis, Thomas J W Rowntree, Yue Guan, Matthew A Brash, Kurt DrickamerAbstract:Background: Mincle facilitates establishment of persistent infections of macrophages by Mycobacterium tuberculosis. Results: The mechanism of mincle binding to mycobacterial glycolipids has been defined, and inhibitors have been synthesized. Conclusion: Mincle binds to both the sugar portion of the glycolipid and the hydrocarbon tail. Significance: The results suggest ways to manipulate the response to mycobacteria and to improve adjuvants that stimulate the immune system. Binding of the macrophage lectin mincle to Trehalose Dimycolate, a key glycolipid virulence factor on the surface of Mycobacterium tuberculosis and Mycobacterium bovis, initiates responses that can lead both to toxicity and to protection of these pathogens from destruction. Crystallographic structural analysis, site-directed mutagenesis, and binding studies with glycolipid mimics have been used to define an extended binding site in the C-type carbohydrate recognition domain (CRD) of bovine mincle that encompasses both the headgroup and a portion of the attached acyl chains. One glucose residue of the Trehalose Glcα1–1Glcα headgroup is liganded to a Ca2+ in a manner common to many C-type CRDs, whereas the second glucose residue is accommodated in a novel secondary binding site. The additional contacts in the secondary site lead to a 36-fold higher affinity for Trehalose compared with glucose. An adjacent hydrophobic groove, not seen in other C-type CRDs, provides a docking site for one of the acyl chains attached to the Trehalose, which can be targeted with small molecule analogs of Trehalose Dimycolate that bind with 52-fold higher affinity than Trehalose. The data demonstrate how mincle bridges between the surfaces of the macrophage and the mycobacterium and suggest the possibility of disrupting this interaction. In addition, the results may provide a basis for design of adjuvants that mimic the ability of mycobacteria to stimulate a response to immunization that can be employed in vaccine development.
Fiona Mcintosh - One of the best experts on this subject based on the ideXlab platform.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns partially complete Freund’s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel BehrAbstract:Complete Freund's adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMps) to study mycobacterial immunity and immunopathogenesis.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns work synergistically to recapitulate complete Freund\'s adjuvant
2019Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Abstract Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to induce experimental autoimmunity qualitatively similar to the whole mycobacteria in CFA. This research outlines how to replace CFA with a consistent, molecularly defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
Marcel A Behr - One of the best experts on this subject based on the ideXlab platform.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns work synergistically to recapitulate complete Freund\'s adjuvant
2019Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Abstract Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to induce experimental autoimmunity qualitatively similar to the whole mycobacteria in CFA. This research outlines how to replace CFA with a consistent, molecularly defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
Jerome Nigou - One of the best experts on this subject based on the ideXlab platform.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns partially complete Freund’s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel BehrAbstract:Complete Freund's adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMps) to study mycobacterial immunity and immunopathogenesis.
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synthetic mycobacterial molecular patterns partially complete freund s adjuvant
Scientific Reports, 2020Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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Synthetic mycobacterial molecular patterns work synergistically to recapitulate complete Freund\'s adjuvant
2019Co-Authors: Jeanyves Dube, Fiona Mcintosh, Juan G Zarruk, Jerome Nigou, Samuel David, Marcel A BehrAbstract:Abstract Complete Freund’s adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus Trehalose Dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal Trehalose Dimycolate motif GlcC14C18 was able to induce experimental autoimmunity qualitatively similar to the whole mycobacteria in CFA. This research outlines how to replace CFA with a consistent, molecularly defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
