1887

Abstract

Secondary sigma factors in bacteria direct transcription of defence regulons in response to specific stresses. To identify which sigma factors in the human respiratory pathogen are important for adaptive survival , defined null mutations were created in individual sigma factor genes. In this study, growth virulence and guinea pig pathology of mutants lacking functional sigma factors (SigC, SigF, or SigM) were compared to the parent strain, H37Rv. None of the mutant strains exhibited a growth deficiency in Middlebrook 7H9 broth, nor were any impaired for intracellular replication in the human monocytic macrophage cell-line THP-1. Following low-dose aerosol infection of guinea pigs, however, differences could be detected. While a SigM mutant resulted in lung and spleen granulomas of comparable composition to those found in H37Rv-infected animals, a SigF mutant was partially attenuated, exhibiting necrotic spleen granulomas and ill-defined lung granulomas. SigC mutants exhibited attenuation in the lung and spleen; notably, necrotic granulomas were absent. These data suggest that while SigF may be important for survival in the lung, SigC is likely a key regulator of pathogenesis and adaptive survival in the lung and spleen. Understanding how SigC mediates survival in the host should prove useful in the development of anti-tuberculosis therapies.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.28591-0
2006-06-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/micro/152/6/1591.html?itemId=/content/journal/micro/10.1099/mic.0.28591-0&mimeType=html&fmt=ahah

References

  1. Ando M, Yoshimatsu T, Ko C, Converse P. J, Bishai W. R. 2003; Deletion of M. tuberculosis sigma factor E results in delayed time to death with bacterial persistence in the lungs of aerosol-infected mice. Infect Immun 71:7170–7172 [CrossRef]
    [Google Scholar]
  2. Baldwin S. L, D'Souza C, Roberts A. D. 7 other authors 1998; Evaluation of new vaccines in the mouse and guinea pig model of TB. Infect Immun 66:2951–2959
    [Google Scholar]
  3. Chen P, Ruiz R. E, Li Q, Silver R. F, Bishai W. R. 2000; Construction and characterization of a M. tuberculosis mutant lacking the alternate sigma factor gene, sigF . Infect Immun 68:5575–5580 [CrossRef]
    [Google Scholar]
  4. Cole S. T, Brosch R, Parkhill J. 38 other authors 1998; Deciphering the biology of M. tuberculosis from the complete genome sequence. Nature 393:537–544 [CrossRef]
    [Google Scholar]
  5. Cotran R. S, Kumar V, Collins T. 1999 Robbins Pathologic Basis of Disease, 6th edn.. Philadelphia, PA: W. B. Saunders;
    [Google Scholar]
  6. Dye C, Scheele S, Dolin P, Pathania V, Raviglione M. C. 1999; Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282:677–686 [CrossRef]
    [Google Scholar]
  7. Erickson J. W, Gross C. A. 1989; Identification of the σ [sup]E[/sup] subunit of Escherichia coli RNA polymerase: a second alternate σ factor involved in high-temperature gene expression. Genes Dev 1:419–432
    [Google Scholar]
  8. Geiman D. E, Kaushal D, Ko C. 8 other authors 2004; Attenuation of late-stage disease in mice infected by the M. tuberculosis mutant lacking the SigF alternate sigma factor and identification of SigF-dependent genes by microarray analysis. Infect Immun 72:1733–1745 [CrossRef]
    [Google Scholar]
  9. Gonzalez-Juarrero M, Turner O. C, Turner J, Marietta P, Brooks J. V, Orme I. M. 2001; Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with M. tuberculosis . Infect Immun 69:1722–1728 [CrossRef]
    [Google Scholar]
  10. Hu Y, Kendall S, Stoker N. G, Coates A. R. 2004; The M. tuberculosis sigJ gene controls sensitivity of the bacterium to hydrogen peroxide. FEMS Microbiol Lett 237:415–423
    [Google Scholar]
  11. Kaushal D, Schroeder B. G, Tyagi S. 8 other authors 2002; Reduced immunopathology and mortality despite tissue persistence in a M. tuberculosis mutant lacking alternative sigma factor, SigH. Proc Natl Acad Sci U S A 99:8330–8335 [CrossRef]
    [Google Scholar]
  12. Kong D, Kunimoto D. Y. 1995; Secretion of human interleukin 2 by recombinant M. bovis BCG. Infect Immun 63:799–803
    [Google Scholar]
  13. Manganelli R, Voskuil M. I, Schoolnik G. K, Smith I. 2001; The M. tuberculosis ECF sigma factor σ [sup]E[/sup]: role in global gene expression and survival in macrophages. Mol Microbiol 41:423–437 [CrossRef]
    [Google Scholar]
  14. Manganelli R, Fattorini L, Tan D, Iona E, Orefici G, Altavilla G, Cusatelli P, Smith I. 2004; The extra cytoplasmic function sigma factor σ [sup]E[/sup] is essential for M. tuberculosis virulence in mice. Infect Immun 72:3038–3041 [CrossRef]
    [Google Scholar]
  15. McMurray D. N, Collins F. M, Smith D. W, Dannenberg A. M., Jr. 1996; Pathogenesis of experimental TB in animal models. Curr Top Microbiol Immunol 215:157–179
    [Google Scholar]
  16. Orme I. M, McMurray D. N, Belisle J. T. 2001; Tuberculosis vaccine development: recent progress. Trends Microbiol 9:115–118 [CrossRef]
    [Google Scholar]
  17. Parish T, Stoker N. G. 2000; Use of a flexible cassette method to generate a double unmarked M. tuberculosis tlyA plcABC mutant by gene replacement. Microbiology 146:1969–1975
    [Google Scholar]
  18. Pelicic V, Jackson M, Reyrat J. M, Gicquel B, Guilhot C, Jacobs W. R., Jr. 1997; Efficient allelic exchange and transposon mutagenesis in M. tuberculosis . Proc Natl Acad Sci U S A 94:10955–10960 [CrossRef]
    [Google Scholar]
  19. Raman S, Hazra R, Dascher C. C, Husson R. N. 2004; Transcription regulation by the M. tuberculosis alternative sigma factor SigD and its role in virulence. J Bacteriol 186:6605–6616 [CrossRef]
    [Google Scholar]
  20. Rhoades E. R, Frank A. A, Orme I. M. 1997; Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent M. tuberculosis . Tubercle Lung Dis 78:57–65 [CrossRef]
    [Google Scholar]
  21. Ridley D. S, Ridley M. J. 1987; Rationale for the histological spectrum of TB. A basis for classification. Pathology 19:186–192 [CrossRef]
    [Google Scholar]
  22. Rodrigues L, Smith P. G. 1990; Tuberculosis in developing countries and methods for its control. Trans R Soc Trop Med Hyg 84:739–744 [CrossRef]
    [Google Scholar]
  23. Sassetti C. M, Boyd D. H, Rubin E. J. 2003; Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48:77–84 [CrossRef]
    [Google Scholar]
  24. Sun R, Converse P. J, Ko C, Tyagi S, Morrison N. E, Bishai W. R. 2004; M. tuberculosis ECF sigma factor SigC is required for lethality in mice and for the conditional expression of a defined gene set. Mol Microbiol 52:25–38 [CrossRef]
    [Google Scholar]
  25. Turner O. C, Basaraba R. J, Orme I. M. 2003; Immunopathology of pulmonary granulomas in the guinea pig after infection with M. tuberculosis . Infect Immun 71:864–871 [CrossRef]
    [Google Scholar]
  26. Wiegeshaus E. H, McMurray D. N, Grover A. A, Harding G. E, Smith D. W. 1970; Host-parasite relationships in experimental airborne TB. III. Relevance of microbial enumeration to acquired resistance in guinea pigs. Am Rev Respir Dis 102:422–429
    [Google Scholar]
  27. World Health Organization 1979; Trial of BCG vaccines in South India for TB prevention. WHO Bull 57:810–827
    [Google Scholar]
  28. World Health Organization 2005; Fact sheet no. 104 (revised April 2005). Tuberculosis http://www.who.int/mediacentre/factsheets/fs104/en/print.html
    [Google Scholar]
  29. Yuan Y, Crane D. D, Simpson R. M, Zhu Y. Q, Hickey M. J, Sherman D. R, Barry C. E 3rd. 1998; The 16-kDa alpha-crystallin (Acr) protein of M. tuberculosis is required for growth in macrophages. Proc Natl Acad Sci U S A 95:9578–9583 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.28591-0
Loading
/content/journal/micro/10.1099/mic.0.28591-0
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