Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Tiruviluamala, P. & Reichman, L. B. Tuberculosis. Annu. Rev. Publ. Health 23, 403–426 (2002)

    Article  Google Scholar 

  2. Sreevatsan, S. et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc. Natl Acad. Sci. USA 94, 9869–9874 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fleischmann, R. D. et al. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J. Bacteriol. 184, 5479–5490 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. North, R. J., Ryan, L., LaCource, R., Mogues, T. & Goodrich, M. E. Growth rate of mycobacteria in mice as an unreliable indicator of mycobacterial virulence. Infect. Immun. 67, 5483–5485 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Manca, C. et al. Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates. J. Immunol. 162, 6740–6746 (1999)

    CAS  PubMed  Google Scholar 

  6. Manca, C. et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β. Proc. Natl Acad. Sci. USA 98, 5752–5757 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Valway, S. E. et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N. Engl. J. Med. 338, 633–639 (1998)

    Article  CAS  PubMed  Google Scholar 

  8. Bifani, P. J., Mathema, B., Kurepina, N. E. & Kreiswirth, B. N. Global dissemination of the Mycobacterium tuberculosis W-Beijing family strains. Trends Microbiol. 10, 45–52 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Glynn, J. R., Whiteley, J., Bifani, P. J., Kremer, K. & van Soolingen, D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg. Infect. Dis. 8, 843–849 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Manca, C. et al. Differential monocyte activation underlies strain specific M. tuberculosis pathogenesis. Infect. Immun. (in the press)

  12. Cox, J. S., Chen, B., McNeil, M. & Jacobs, W. R. Jr Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402, 79–83 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Sirakova, T. D., Thirumala, A. K., Dubey, V. S., Sprecher, H. & Kolattukudy, P. E. The Mycobacterium tuberculosis pks2 gene encodes the synthase for the hepta- and octamethyl-branched fatty acids required for sulfolipid synthesis. J. Biol. Chem. 276, 16833–16839 (2001)

    Article  CAS  PubMed  Google Scholar 

  14. Constant, P. et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methly esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem. 277, 38148–38158 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Marmiesse, M. et al. Macro-array and bioinformatic analyses reveal mycobacterial ‘core’ genes, variation in the ESAT-6 gene family and new phylogenetic markers for the Mycobacterium tuberculosis complex. Microbiol. 150, 483–496 (2004)

    Article  CAS  Google Scholar 

  16. Kolattukudy, P. E., Fernandes, N. D., Azad, A. K., Fitzmaurice, A. M. & Sirakova, T. D. Biochemistry and molecular genetics of cell-wall lipid biosynthesis in mycobacteria. Mol. Microbiol. 24, 263–270 (1997)

    Article  CAS  PubMed  Google Scholar 

  17. Vergne, I. I. & Daffe, M. Interaction of mycobacterial glycolipids with host cells. Front. Biosci. 3, 865–876 (1998)

    Article  Google Scholar 

  18. Hunter, S. W. & Brennan, P. J. A novel phenolic glycolipid from Mycobacterium leprae possibly involved in immunogenicity and pathogenicity. J. Bacteriol. 147, 728–735 (1981)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mehra, V., Brennan, P. J., Rada, E., Convit, J. & Bloom, B. R. Lymphocyte suppression in leprosy induced by unique M. leprae glycolipid. Nature 308, 194–196 (1984)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Fournie, J.-J., Adams, E., Mullins, R. J. & Basten, A. Inhibition of human lymphoproliferative responses by mycobacterial phenolic glycolipids. Infect. Immun. 57, 3653–3659 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Vachula, K., Holzer, T. J. & Andersen, B. R. suppression of monocyte oxidative responses by phenolic glycolipid 1 of Mycobacterium leprae. J. Immunol. 142, 1696–1701 (1989)

    CAS  PubMed  Google Scholar 

  22. Silva, C. L., Faccioli, L. H. & Foss, N. T. Suppression of human monocyte cytokine release by phenolic glycolipid-1 of Mycobacterium leprae. Int. J. Lepr. 61, 107–108 (1993)

    CAS  Google Scholar 

  23. Hashimoto, K. et al. Mycobacterium leprae infection in monocyte-derived dendritic cells and its influence on antigen-presenting function. Infect. Immun. 70, 5167–5176 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ng, V. et al. Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103, 511–524 (2000)

    Article  CAS  PubMed  Google Scholar 

  25. Stover, C. K. et al. New use of BCG for recombinant vaccines. Nature 351, 456–460 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003)

    Article  CAS  Google Scholar 

  27. Garbe, T. R. et al. Transformation of mycobacterial species using hygromycin resistance as selectable marker. Microbiol. 140, 133–138 (1994)

    Article  CAS  Google Scholar 

  28. Pelicic, V. et al. Efficient allelic exchange and transposon mutagenesis in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 94, 10955–10960 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. O'Gaora, P. et al. Mycobacteria as immunogens: development of expression vectors for use in multiple mycobacterial species. Med. Princ. Prac. 6, 91–96 (1997)

    Article  Google Scholar 

  30. Slayden, R. A. & Barry, C. E. III in Mycobacterium tuberculosis protocols (eds Parish, T. & Stoker, N. G.) 229–245 (Humana, New Jersey, 2001)

    Book  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Clifton E. Barry III.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing