Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 May 29;355(1397):657–665. doi: 10.1098/rstb.2000.0606

Virulence gene regulation inside and outside.

V J DiRita 1, N C Engleberg 1, A Heath 1, A Miller 1, J A Crawford 1, R Yu 1
PMCID: PMC1692771  PMID: 10874738

Abstract

Much knowledge about microbial gene regulation and virulence is derived from genetic and biochemical studies done outside of hosts. The aim of this review is to correlate observations made in vitro and in vivo with two different bacterial pathogens in which the nature of regulated gene expression leading to virulence is quite different. The first is Vibrio cholerae, in which the concerted action of a complicated regulatory cascade involving several transcription activators leads ultimately to expression of cholera toxin and the toxin-coregulated pilus. The regulatory cascade is active in vivo and is also required for maintenance of V. cholerae in the intestinal tract during experimental infection. Nevertheless, specific signals predicted to be generated in vivo, such as bile and a temperature of 37 degrees C, have a severe down-modulating effect on activation of toxin and pilus expression. Another unusual aspect of gene regulation in this system is the role played by inner membrane proteins that activate transcription. Although the topology of these proteins suggests an appealing model for signal transduction leading to virulence gene expression, experimental evidence suggests that such a model may be simplistic. In Streptococcus pyogenes, capsule production is critical for virulence in an animal model of necrotizing skin infection. Yet capsule is apparently produced to high levels only from mutation in a two-component regulatory system, CsrR and CsrS. Thus it seems that in V. cholerae a complex regulatory pathway has evolved to control virulence by induction of gene expression in vivo, whereas in S. pyogenes at least one mode of pathogenicity is potentiated by the absence of regulation.

Full Text

The Full Text of this article is available as a PDF (246.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akerley B. J., Cotter P. A., Miller J. F. Ectopic expression of the flagellar regulon alters development of the Bordetella-host interaction. Cell. 1995 Feb 24;80(4):611–620. doi: 10.1016/0092-8674(95)90515-4. [DOI] [PubMed] [Google Scholar]
  2. Akerley B. J., Miller J. F. Understanding signal transduction during bacterial infection. Trends Microbiol. 1996 Apr;4(4):141–146. doi: 10.1016/0966-842x(96)10024-x. [DOI] [PubMed] [Google Scholar]
  3. Ashbaugh C. D., Warren H. B., Carey V. J., Wessels M. R. Molecular analysis of the role of the group A streptococcal cysteine protease, hyaluronic acid capsule, and M protein in a murine model of human invasive soft-tissue infection. J Clin Invest. 1998 Aug 1;102(3):550–560. doi: 10.1172/JCI3065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernish B., van de Rijn I. Characterization of a two-component system in Streptococcus pyogenes which is involved in regulation of hyaluronic acid production. J Biol Chem. 1999 Feb 19;274(8):4786–4793. doi: 10.1074/jbc.274.8.4786. [DOI] [PubMed] [Google Scholar]
  5. Brown R. C., Taylor R. K. Organization of tcp, acf, and toxT genes within a ToxT-dependent operon. Mol Microbiol. 1995 May;16(3):425–439. doi: 10.1111/j.1365-2958.1995.tb02408.x. [DOI] [PubMed] [Google Scholar]
  6. Bunce C., Wheeler L., Reed G., Musser J., Barg N. Murine model of cutaneous infection with gram-positive cocci. Infect Immun. 1992 Jul;60(7):2636–2640. doi: 10.1128/iai.60.7.2636-2640.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Callahan L. T., 3rd, Richardson S. H. Biochemistry of Vibrio cholerae virulence. 3. Nutritional requirements for toxin production and the effects of pH on toxin elaboration in chemically defined media. Infect Immun. 1973 Apr;7(4):567–572. doi: 10.1128/iai.7.4.567-572.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Champion G. A., Neely M. N., Brennan M. A., DiRita V. J. A branch in the ToxR regulatory cascade of Vibrio cholerae revealed by characterization of toxT mutant strains. Mol Microbiol. 1997 Jan;23(2):323–331. doi: 10.1046/j.1365-2958.1997.2191585.x. [DOI] [PubMed] [Google Scholar]
  9. Dell C. L., Neely M. N., Olson E. R. Altered pH and lysine signalling mutants of cadC, a gene encoding a membrane-bound transcriptional activator of the Escherichia coli cadBA operon. Mol Microbiol. 1994 Oct;14(1):7–16. doi: 10.1111/j.1365-2958.1994.tb01262.x. [DOI] [PubMed] [Google Scholar]
  10. DiRita V. J., Mekalanos J. J. Periplasmic interaction between two membrane regulatory proteins, ToxR and ToxS, results in signal transduction and transcriptional activation. Cell. 1991 Jan 11;64(1):29–37. doi: 10.1016/0092-8674(91)90206-e. [DOI] [PubMed] [Google Scholar]
  11. DiRita V. J., Neely M., Taylor R. K., Bruss P. M. Differential expression of the ToxR regulon in classical and E1 Tor biotypes of Vibrio cholerae is due to biotype-specific control over toxT expression. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7991–7995. doi: 10.1073/pnas.93.15.7991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DiRita V. J., Parsot C., Jander G., Mekalanos J. J. Regulatory cascade controls virulence in Vibrio cholerae. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5403–5407. doi: 10.1073/pnas.88.12.5403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dorman C. J., Porter M. E. The Shigella virulence gene regulatory cascade: a paradigm of bacterial gene control mechanisms. Mol Microbiol. 1998 Aug;29(3):677–684. doi: 10.1046/j.1365-2958.1998.00902.x. [DOI] [PubMed] [Google Scholar]
  14. Evans D. J., Jr, Richardson S. H. In vitro production of choleragen and vascular permeability factor by Vibrio cholerae. J Bacteriol. 1968 Jul;96(1):126–130. doi: 10.1128/jb.96.1.126-130.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. García Véscovi E., Soncini F. C., Groisman E. A. Mg2+ as an extracellular signal: environmental regulation of Salmonella virulence. Cell. 1996 Jan 12;84(1):165–174. doi: 10.1016/s0092-8674(00)81003-x. [DOI] [PubMed] [Google Scholar]
  16. Gupta S., Chowdhury R. Bile affects production of virulence factors and motility of Vibrio cholerae. Infect Immun. 1997 Mar;65(3):1131–1134. doi: 10.1128/iai.65.3.1131-1134.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heath A., DiRita V. J., Barg N. L., Engleberg N. C. A two-component regulatory system, CsrR-CsrS, represses expression of three Streptococcus pyogenes virulence factors, hyaluronic acid capsule, streptolysin S, and pyrogenic exotoxin B. Infect Immun. 1999 Oct;67(10):5298–5305. doi: 10.1128/iai.67.10.5298-5305.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Higgins D. E., DiRita V. J. Transcriptional control of toxT, a regulatory gene in the ToxR regulon of Vibrio cholerae. Mol Microbiol. 1994 Oct;14(1):17–29. doi: 10.1111/j.1365-2958.1994.tb01263.x. [DOI] [PubMed] [Google Scholar]
  19. Häse C. C., Mekalanos J. J. Effects of changes in membrane sodium flux on virulence gene expression in Vibrio cholerae. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3183–3187. doi: 10.1073/pnas.96.6.3183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Häse C. C., Mekalanos J. J. TcpP protein is a positive regulator of virulence gene expression in Vibrio cholerae. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):730–734. doi: 10.1073/pnas.95.2.730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kolmar H., Hennecke F., Götze K., Janzer B., Vogt B., Mayer F., Fritz H. J. Membrane insertion of the bacterial signal transduction protein ToxR and requirements of transcription activation studied by modular replacement of different protein substructures. EMBO J. 1995 Aug 15;14(16):3895–3904. doi: 10.1002/j.1460-2075.1995.tb00061.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kovacikova G., Skorupski K. A Vibrio cholerae LysR homolog, AphB, cooperates with AphA at the tcpPH promoter to activate expression of the ToxR virulence cascade. J Bacteriol. 1999 Jul;181(14):4250–4256. doi: 10.1128/jb.181.14.4250-4256.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Levin J. C., Wessels M. R. Identification of csrR/csrS, a genetic locus that regulates hyaluronic acid capsule synthesis in group A Streptococcus. Mol Microbiol. 1998 Oct;30(1):209–219. doi: 10.1046/j.1365-2958.1998.01057.x. [DOI] [PubMed] [Google Scholar]
  24. Li C. C., Crawford J. A., DiRita V. J., Kaper J. B. Molecular cloning and transcriptional regulation of ompT, a ToxR-repressed gene in Vibrio cholerae. Mol Microbiol. 2000 Jan;35(1):189–203. doi: 10.1046/j.1365-2958.2000.01699.x. [DOI] [PubMed] [Google Scholar]
  25. Maurelli A. T., Blackmon B., Curtiss R., 3rd Temperature-dependent expression of virulence genes in Shigella species. Infect Immun. 1984 Jan;43(1):195–201. doi: 10.1128/iai.43.1.195-201.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maurelli A. T., Curtiss R., 3rd Bacteriophage Mu d1(Apr lac) generates vir-lac operon fusions in Shigella flexneri 2a. Infect Immun. 1984 Sep;45(3):642–648. doi: 10.1128/iai.45.3.642-648.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Maurelli A. T., Sansonetti P. J. Identification of a chromosomal gene controlling temperature-regulated expression of Shigella virulence. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2820–2824. doi: 10.1073/pnas.85.8.2820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Medrano A. I., DiRita V. J., Castillo G., Sanchez J. Transient transcriptional activation of the Vibrio cholerae El Tor virulence regulator toxT in response to culture conditions. Infect Immun. 1999 May;67(5):2178–2183. doi: 10.1128/iai.67.5.2178-2183.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Miller J. F., Johnson S. A., Black W. J., Beattie D. T., Mekalanos J. J., Falkow S. Constitutive sensory transduction mutations in the Bordetella pertussis bvgS gene. J Bacteriol. 1992 Feb;174(3):970–979. doi: 10.1128/jb.174.3.970-979.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Miller V. L., DiRita V. J., Mekalanos J. J. Identification of toxS, a regulatory gene whose product enhances toxR-mediated activation of the cholera toxin promoter. J Bacteriol. 1989 Mar;171(3):1288–1293. doi: 10.1128/jb.171.3.1288-1293.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Miller V. L., Mekalanos J. J. A novel suicide vector and its use in construction of insertion mutations: osmoregulation of outer membrane proteins and virulence determinants in Vibrio cholerae requires toxR. J Bacteriol. 1988 Jun;170(6):2575–2583. doi: 10.1128/jb.170.6.2575-2583.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miller V. L., Mekalanos J. J. Synthesis of cholera toxin is positively regulated at the transcriptional level by toxR. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3471–3475. doi: 10.1073/pnas.81.11.3471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Miller V. L., Taylor R. K., Mekalanos J. J. Cholera toxin transcriptional activator toxR is a transmembrane DNA binding protein. Cell. 1987 Jan 30;48(2):271–279. doi: 10.1016/0092-8674(87)90430-2. [DOI] [PubMed] [Google Scholar]
  34. Murley Y. M., Carroll P. A., Skorupski K., Taylor R. K., Calderwood S. B. Differential transcription of the tcpPH operon confers biotype-specific control of the Vibrio cholerae ToxR virulence regulon. Infect Immun. 1999 Oct;67(10):5117–5123. doi: 10.1128/iai.67.10.5117-5123.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ottemann K. M., Mekalanos J. J. Analysis of Vibrio cholerae ToxR function by construction of novel fusion proteins. Mol Microbiol. 1995 Feb;15(4):719–731. doi: 10.1111/j.1365-2958.1995.tb02380.x. [DOI] [PubMed] [Google Scholar]
  36. Parkinson J. S., Kofoid E. C. Communication modules in bacterial signaling proteins. Annu Rev Genet. 1992;26:71–112. doi: 10.1146/annurev.ge.26.120192.000443. [DOI] [PubMed] [Google Scholar]
  37. Parkinson J. S. Signal transduction schemes of bacteria. Cell. 1993 Jun 4;73(5):857–871. doi: 10.1016/0092-8674(93)90267-t. [DOI] [PubMed] [Google Scholar]
  38. Pearson G. D., Mekalanos J. J. Molecular cloning of Vibrio cholerae enterotoxin genes in Escherichia coli K-12. Proc Natl Acad Sci U S A. 1982 May;79(9):2976–2980. doi: 10.1073/pnas.79.9.2976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Peterson K. M., Mekalanos J. J. Characterization of the Vibrio cholerae ToxR regulon: identification of novel genes involved in intestinal colonization. Infect Immun. 1988 Nov;56(11):2822–2829. doi: 10.1128/iai.56.11.2822-2829.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Richardson S. H. Factors influencing in vitro skin permeability factor production by Vibrio cholerae. J Bacteriol. 1969 Oct;100(1):27–34. doi: 10.1128/jb.100.1.27-34.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schuhmacher D. A., Klose K. E. Environmental signals modulate ToxT-dependent virulence factor expression in Vibrio cholerae. J Bacteriol. 1999 Mar;181(5):1508–1514. doi: 10.1128/jb.181.5.1508-1514.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Skorupski K., Taylor R. K. A new level in the Vibrio cholerae ToxR virulence cascade: AphA is required for transcriptional activation of the tcpPH operon. Mol Microbiol. 1999 Feb;31(3):763–771. doi: 10.1046/j.1365-2958.1999.01215.x. [DOI] [PubMed] [Google Scholar]
  43. Skorupski K., Taylor R. K. Control of the ToxR virulence regulon in Vibrio cholerae by environmental stimuli. Mol Microbiol. 1997 Sep;25(6):1003–1009. doi: 10.1046/j.1365-2958.1997.5481909.x. [DOI] [PubMed] [Google Scholar]
  44. Véscovi E. G., Ayala Y. M., Di Cera E., Groisman E. A. Characterization of the bacterial sensor protein PhoQ. Evidence for distinct binding sites for Mg2+ and Ca2+. J Biol Chem. 1997 Jan 17;272(3):1440–1443. doi: 10.1074/jbc.272.3.1440. [DOI] [PubMed] [Google Scholar]
  45. Wren B. W., Colby S. M., Cubberley R. R., Pallen M. J. Degenerate PCR primers for the amplification of fragments from genes encoding response regulators from a range of pathogenic bacteria. FEMS Microbiol Lett. 1992 Dec 1;78(2-3):287–291. doi: 10.1016/0378-1097(92)90042-m. [DOI] [PubMed] [Google Scholar]
  46. Yu R. R., DiRita V. J. Analysis of an autoregulatory loop controlling ToxT, cholera toxin, and toxin-coregulated pilus production in Vibrio cholerae. J Bacteriol. 1999 Apr;181(8):2584–2592. doi: 10.1128/jb.181.8.2584-2592.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES