A Sulfated Metabolite Produced by stf3 Negatively Regulates the Virulence of Mycobacterium tuberculosis

Sulfated molecules have been shown to modulate isotypic interactions between cells of metazoans and heterotypic interactions between bacterial pathogens or symbionts and their eukaryotic host cells. Mycobacterium tuberculosis, the causative agent of tuberculosis, produces sulfated molecules that hav...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 103; no. 11; pp. 4258 - 4263
Main Authors Mougous, Joseph D., Senaratne, Ryan H., Petzold, Christopher J., Jain, Madhulika, Lee, Dong H., Schelle, Michael W., Leavell, Michael D., Cox, Jeffery S., Leary, Julie A., Riley, Lee W., Bertozzi, Carolyn R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 14.03.2006
Subjects
Animals
Bacteria
Biological Sciences
Biosynthesis
Female
Gene Deletion
Genes, Bacterial
Infections
Lung - microbiology
Lungs
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microbiology
Molecules
Mutation
Mycobacterium tuberculosis
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - metabolism
Mycobacterium tuberculosis - pathogenicity
Sulfates
Sulfates - metabolism
Sulfation
Sulfotransferases - genetics
Sulfotransferases - metabolism
Tuberculosis
Tuberculosis, Pulmonary - microbiology
Virulence
Virulence - genetics
Virulence - physiology
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Summary:Sulfated molecules have been shown to modulate isotypic interactions between cells of metazoans and heterotypic interactions between bacterial pathogens or symbionts and their eukaryotic host cells. Mycobacterium tuberculosis, the causative agent of tuberculosis, produces sulfated molecules that have eluded functional characterization for decades. We demonstrate here that a previously uncharacterized sulfated molecule, termed 5881, is localized to the outer envelope of M. tuberculosis and negatively regulates the virulence of the organism in two mouse infection models. Furthermore, we show that the biosynthesis of 5881 relies on the universal sulfate donor 3'-phosphoadenosine-5'-phosphosulfate and a previously uncharacterized sulfotransferase, stf3. These findings extend the known functions of sulfated molecules as general modulators of cell-cell interactions to include those between a bacterium and a human host.
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Present address: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Author contributions: J.D.M., R.H.S., C.J.P., M.J., M.W.S., J.S.C., J.A.L., L.W.R., and C.R.B. designed research; J.D.M., R.H.S., C.J.P., D.H.L., M.W.S., and M.D.L. performed research; J.D.M., C.J.P., and M.J. contributed new reagents/analytic tools; J.D.M. and M.W.S. analyzed data; and J.D.M., M.W.S., and C.R.B. wrote the paper.
Contributed by Carolyn R. Bertozzi, January 19, 2006
Present address: Department of Chemistry and Division of Molecular Cellular Biology, Genome Center, University of California, Davis, CA 95616.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510861103