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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 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 outcomes4,5,6,7. 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.

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Figure 1: PGL is produced by HN878 and related W-Beijing strains.
Figure 2: PGL is responsible for the hypervirulent phenotype of HN878 in mice.
Figure 3: PGL-mediated inhibition of pro-inflammatory cytokine release by murine BMMs.

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Acknowledgements

The authors wish to thank J. Gonzales and M. Goodwin for their assistance with animal studies and NMR spectroscopy, respectively. G.K. is supported by grants from the NIH.

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Correspondence to Clifton E. Barry III.

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Reed, M., Domenech, P., Manca, C. et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84–87 (2004). https://doi.org/10.1038/nature02837

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