1887

Abstract

Genome sequencing of complex members has accelerated the search for new disease-control tools. Antigen mining is one area that has benefited enormously from access to genome data. As part of an ongoing antigen mining programme, we screened genes that were previously identified by transcriptome analysis as upregulated in response to an acid shock for their expression profile and antigenicity. We show that the genes encoding two methyltransferases, and , were highly upregulated in a mouse model of infection, and were antigenic in -infected cattle. As the genes encoding these antigens were highly upregulated , we sought to define their genetic regulation. A mutant was constructed that was deleted for their putative regulator, ; loss of the regulator led to increased expression of the flanking methyltransferases and a defined set of distal genes. This work has therefore generated both applied and fundamental outputs, with the description of novel mycobacterial antigens that can now be moved into field trials, but also with the description of a regulatory network that is responsive to both and stimuli.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.2007/014548-0
2008-04-01
2020-10-01
Loading full text...

Full text loading...

/deliver/fulltext/micro/154/4/1059.html?itemId=/content/journal/micro/10.1099/mic.0.2007/014548-0&mimeType=html&fmt=ahah

References

  1. Bacon J., James B. W., Wernisch L., Williams A., Morley K. A., Hatch G. J., Mangan J. A., Hinds J., Stoker N. G.. other authors 2004; The influence of reduced oxygen availability on pathogenicity and gene expression in Mycobacterium tuberculosis. Tuberculosis (Edinb84:205–217
    [Google Scholar]
  2. Cockle P. J., Gordon S. V., Lalvani A., Buddle B. M., Hewinson R. G., Vordermeier H. M.. 2002; Identification of novel Mycobacterium tuberculosis antigens with potential as diagnostic reagents or subunit vaccine candidates by comparative genomics. Infect Immun70:6996–7003
    [Google Scholar]
  3. Cole S. T., Brosch R., Parkhill J., Garnier T., Churcher C., Harris D., Gordon S. V., Eiglmeier K., Gas S.. other authors 1998; Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature393:537–544
    [Google Scholar]
  4. Donnelly-Wu M. K., Jacobs W. R. Jr, Hatfull G. F.. 1993; Superinfection immunity of mycobacteriophage L5: applications for genetic transformation of mycobacteria. Mol Microbiol7:407–417
    [Google Scholar]
  5. Ellison D. W., Miller V. L.. 2006; Regulation of virulence by members of the MarR/SlyA family. Curr Opin Microbiol9:153–159
    [Google Scholar]
  6. Garnier T., Eiglmeier K., Camus J. C., Medina N., Mansoor H., Pryor M., Duthoy S., Grondin S., Lacroix C.. other authors 2003; The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U S A100:7877–7882
    [Google Scholar]
  7. Glickman M. S., Cox J. S., Jacobs W. R. Jr. 2000; A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell5:717–727
    [Google Scholar]
  8. Golby P., Hatch K. A., Bacon J., Cooney R., Riley P., Allnutt J., Hinds J., Nunez J., Marsh P. D.. other authors 2007; Comparative transcriptomics reveals key gene expression differences between the human and bovine pathogens of the Mycobacterium tuberculosis complex. Microbiology153:3323–3336
    [Google Scholar]
  9. Grkovic S., Brown M. H., Skurray R. A.. 2002; Regulation of bacterial drug export systems. Microbiol Mol Biol Rev66:671–701
    [Google Scholar]
  10. Ibanga H. B., Brookes R. H., Hill P. C., Owiafe P. K., Fletcher H. A., Lienhardt C., Hill A. V., Adegbola R. A., McShane H.. 2006; Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis6:522–528
    [Google Scholar]
  11. Mahairas G. G., Sabo P. J., Hickey M. J., Singh D. C., Stover C. K.. 1996; Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol178:1274–1282
    [Google Scholar]
  12. Muttucumaru D. G., Roberts G., Hinds J., Stabler R. A., Parish T.. 2004; Gene expression profile of Mycobacterium tuberculosis in a non-replicating state. Tuberculosis (Edinb84:239–246
    [Google Scholar]
  13. Orme I. M.. 2006; Preclinical testing of new vaccines for tuberculosis: a comprehensive review. Vaccine24:2–19
    [Google Scholar]
  14. Pethe K., Alonso S., Biet F., Delogu G., Brennan M. J., Locht C., Menozzi F. D.. 2001; The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature412:190–194
    [Google Scholar]
  15. Pethe K., Bifani P., Drobecq H., Sergheraert C., Debrie A. S., Locht C., Menozzi F. D.. 2002; Mycobacterial heparin-binding hemagglutinin and laminin-binding protein share antigenic methyllysines that confer resistance to proteolysis. Proc Natl Acad Sci U S A99:10759–10764
    [Google Scholar]
  16. Rao V., Gao F., Chen B., Jacobs W. R. Jr, Glickman M. S.. 2006; Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence. J Clin Invest116:1660–1667
    [Google Scholar]
  17. Sassetti C. M., Rubin E. J.. 2003; Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A100:12989–12994
    [Google Scholar]
  18. Skjøt R. L., Oettinger T., Rosenkrands I., Ravn P., Brock I., Jacobsen S., Andersen P.. 2000; Comparative evaluation of low-molecular-mass proteins from Mycobacterium tuberculosis identifies members of the ESAT-6 family as immunodominant T-cell antigens. Infect Immun68:214–220
    [Google Scholar]
  19. Sørensen A. L., Nagai S., Houen G., Andersen P., Andersen A. B.. 1995; Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect Immun63:1710–1717
    [Google Scholar]
  20. Stinear T. P., Seemann T., Pidot S., Frigui W., Reysset G., Garnier T., Meurice G., Simon D., Bouchier C.. other authors 2007; Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer. Genome Res17:192–200
    [Google Scholar]
  21. Temmerman S., Pethe K., Parra M., Alonso S., Rouanet C., Pickett T., Drowart A., Debrie A. S., Delogu G.. other authors 2004; Methylation-dependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin. Nat Med10:935–941
    [Google Scholar]
  22. Vordermeier H. M., Chambers M. A., Buddle B. M., Pollock J. M., Hewinson R. G.. 2006; Progress in the development of vaccines and diagnostic reagents to control. tuberculosis in cattle. Vet J171:229–244
    [Google Scholar]
  23. Voskuil M. I., Visconti K. C., Schoolnik G. K.. 2004; Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. Tuberculosis (Edinb84:218–227
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.2007/014548-0
Loading
/content/journal/micro/10.1099/mic.0.2007/014548-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error