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- Title
A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response.
- Authors
Reed, Michael B.; Domenech, Pilar; Manca, Claudia; Hua Su; Barczak, Amy K.; Kreiswirth, Barry N.; Kaplan, Gilla; Barry III, Clifton E.
- Abstract
Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2–3 million lives from tuberculosis worldwide1. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis2,3, 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 outcomes4–7. 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 family8 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-α 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.
- Subjects
MYCOBACTERIUM tuberculosis; GENETICS; MOLECULES; LIPIDS; POLYKETIDES; BACTERIA; MACROPHAGES
- Publication
Nature, 2004, Vol 431, Issue 7004, p84
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature02837