title: A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response.
abstract: Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2-3 million lives from tuberculosis worldwide. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis, there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes. Here we describe the identification and functional relevance of a highly biologically active lipid species-a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner.
authors.affiliation: Tuberculosis Research Section, NIAID, National Institutes of Health, 12441 Parklawn Drive, Rockville, Maryland 20852, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reed
authors.forename: Pilar
authors.initials: P
authors.lastname: Domenech
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Amy K
authors.initials: AK
authors.lastname: Barczak
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D004195:Disease Models, Animal; D006017:Glycolipids / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000145:classification / Q000276:immunology* / Q000472:pathogenicity*; D010641:Phenotype; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology*; D014774:Virulence
chemical_list: D006017:Glycolipids; D018836:Inflammation Mediators; D009097:Multienzyme Complexes