title: Trisaccharides of Phenolic Glycolipids Confer Advantages to Pathogenic Mycobacteria through Manipulation of Host-Cell Pattern-Recognition Receptors.
abstract: Despite mycobacterial pathogens continue to be a threat to public health, the mechanisms that allow them to persist by modulating the host immune response are poorly understood. Among the factors suspected to play a role are phenolic glycolipids (PGLs), produced notably by the major pathogenic species such as Mycobacterium tuberculosis and Mycobacterium leprae. Here, we report an original strategy combining genetic reprogramming of the PGL pathway in Mycobacterium bovis BCG and chemical synthesis to examine whether sugar variations in the species-specific PGLs have an impact on pattern recognition receptors (PRRs) and the overall response of infected cells. We identified two distinct properties associated with the trisaccharide domains found in the PGLs from M. leprae and M. tuberculosis. First, the sugar moiety of PGL-1 from M. leprae is unique in its capacity to bind the lectin domain of complement receptor 3 (CR3) for efficient invasion of human macrophages. Second, the trisaccharide domain of the PGLs from M. tuberculosis and M. leprae share the capacity to inhibit Toll-like receptor 2 (TLR2)-triggered NF-κB activation, and thus the production of inflammatory cytokines. Consistently, PGL-1 was found to also bind isolated TLR2. By contrast, the simpler sugar domains of PGLs from M. bovis and Mycobacterium ulcerans did not exhibit such activities. In conclusion, the production of extended saccharide domains on PGLs dictates their recognition by host PRRs to enhance mycobacterial infectivity and subvert the host immune response.
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arbués
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Malaga
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Constant
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Prandi
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale) , BP 64182, 31077 Toulouse, France.|Université de Toulouse, UPS , 31077, Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Astarie-Dequeker
mesh_terms: D006017:Glycolipids / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009166:Mycobacterium leprae / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D010636:Phenols / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014312:Trisaccharides / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D006017:Glycolipids; D016328:NF-kappa B; D010636:Phenols; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014312:Trisaccharides