1887

Abstract

Primary infection by group A streptococci (GAS) takes place at either the throat or skin of the human host, often leading to pharyngitis or impetigo, respectively. Many GAS strains differ in their preference for throat and skin tissue sites. Previous epidemiological findings show that many of the strains displaying strong tropism for the skin have a high-affinity binding site for plasminogen, located within M protein (PAM), a prominent surface fibril. Plasminogen bound by PAM interacts with streptokinase, a plasminogen activator secreted by GAS, to yield bacterial-bound plasmin activity. In this study, PAM and streptokinase were tested for their roles in infection using an experimental model that closely mimics human impetigo. Inactivation of genes encoding either PAM or streptokinase led to a partial, but significant, loss of virulence , as measured by net growth of the bacteria and pathological alterations. The relative loss in virulence was greater for the streptokinase mutant than for the PAM mutant. However, the PAM mutant, but not the streptokinase mutant, displayed a partial loss in resistance to phagocytosis . The combined experimental and epidemiological data provide evidence that PAM and streptokinase play a key role in mediating skin-specific infection by GAS. In addition, secreted cysteine proteinase activity due to SpeB leads to degradation of streptokinase in stationary phase broth cultures. Since SpeB is also a determinant of tissue-specific GAS infection at the skin, direct interactions between these two proteolytic pathways may constitute an important pathogenic mechanism. An integrated model for superficial infection at the skin is presented.

Loading

Article metrics loading...

/content/journal/micro/10.1099/00221287-148-12-3933
2002-12-01
2019-12-13
Loading full text...

Full text loading...

/deliver/fulltext/micro/148/12/1483933a.html?itemId=/content/journal/micro/10.1099/00221287-148-12-3933&mimeType=html&fmt=ahah

References

  1. Anderson, R. & May, R. (1991). Infectious Diseases of Humans: Dynamics and Control. Oxford: Oxford University Press.
  2. Anderson, R. M. ( 1998; ). Analytic theory of epidemics. In Emerging Infections , pp. 23-50. Edited by R. M. Krause. New York:Academic Press.
  3. Anthony, B. F., Kaplan, E. L., Wannamaker, L. W. & Chapman, S. S. ( 1976; ). The dynamics of streptococcal infections in a defined population of children: serotypes associated with skin and respiratory infections. Am J Epidemiol 104, 652-666.
    [Google Scholar]
  4. Ashbaugh, C. D. & Wessels, M. R. ( 2001; ). Absence of a cysteine protease effect on bacterial virulence in two murine models of human invasive group A streptococcal infection. Infect Immun 69, 6683-6688.[CrossRef]
    [Google Scholar]
  5. Berge, A. & Björck, L. ( 1995; ). Streptococcal cysteine proteinase releases biologically active fragments of streptococcal surface proteins. J Biol Chem 270, 9862-9867.[CrossRef]
    [Google Scholar]
  6. Berge, A. & Sjöbring, U. ( 1993; ). PAM, a novel plasminogen-binding protein from Streptococcus pyogenes. J Biol Chem 268, 25417-25424.
    [Google Scholar]
  7. Bessen, D. E. & Fischetti, V. A. ( 1992; ). Nucleotide sequences of two adjacent M and M-like protein genes of group A streptococci: different RNA transcript levels and identification of a unique IgA-binding protein. Infect Immun 60, 124-135.
    [Google Scholar]
  8. Bessen, D. E., Sotir, C. M., Readdy, T. L. & Hollingshead, S. K. ( 1996; ). Genetic correlates of throat and skin isolates of group A streptococci. J Infect Dis 173, 896-900.[CrossRef]
    [Google Scholar]
  9. Bessen, D. E., Carapetis, J. R., Beall, B. & 7 other authors ( 2000; ). Contrasting molecular epidemiology of group A streptococci causing tropical and non-tropical infections of the skin and throat. J Infect Dis 182, 1109–1116.[CrossRef]
    [Google Scholar]
  10. Bisno, A. L. & Stevens, D. ( 2000; ). Streptococcus pyogenes (including streptococcal toxic shock syndrome and necrotizing fasciitis). In Principles and Practice of Infectious Diseases , pp. 2101-2117. Edited by G. L. Mandell, R. G. Douglas & R. Dolin. Philadelphia:Churchill Livingstone.
  11. Boyle, M. & Lottenberg, R. ( 1997; ). Plasminogen activation by invasive human pathogens. Thromb Haemostasis 77, 1-10.
    [Google Scholar]
  12. Caparon, M. ( 2000; ). Genetics of group A streptococci. In Gram-Positive Pathogens , pp. 53-65. Edited by V. A. Fischetti, R. P. Novick, J. J. Ferretti, D. A. Portnoy & J. I. Rood. Washington, DC:American Society for Microbiology.
  13. Coleman, J., Gebbia, J., Piesman, J., Degen, J., Bugge, T. & Benach, J. ( 1997; ). Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell 89, 1111-1119.[CrossRef]
    [Google Scholar]
  14. Collin, M. & Olsen, A. ( 2000; ). Generation of a mature streptococcal cysteine proteinase is dependent on cell wall-anchored M1 protein. Mol Microbiol 36, 1306-1318.
    [Google Scholar]
  15. Cunningham, M. W. ( 2000; ). Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13, 470-511.[CrossRef]
    [Google Scholar]
  16. Darmstadt, G., Mentele, L., Podbielski, A. & Rubens, C. ( 2000; ). Role of group A streptococcal virulence factors in adherence to keratinocytes. Infect Immun 68, 1215-1221.[CrossRef]
    [Google Scholar]
  17. Dicuonzo, G., Gherardi, G., Lorino, G., Angeletti, S., DeCesaris, M., Fiscarelli, E., Bessen, D. E. & Beall, B. ( 2001; ). Group A streptococcal genotypes from pediatric throat isolates in Rome, Italy. J Clin Microbiol 39, 1687-1690.[CrossRef]
    [Google Scholar]
  18. Enright, M. C., Spratt, B. G., Kalia, A., Cross, J. H. & Bessen, D. E. ( 2001; ). Multilocus sequence typing of Streptococcus pyogenes and the relationship between emm-type and clone. Infect Immun 69, 2416-2427.[CrossRef]
    [Google Scholar]
  19. Feil, E. J., Holmes, E. C., Bessen, D. E. & 9 other authors ( 2001; ). Recombination within natural populations of pathogenic bacteria: short-term empirical estimates and long-term phylogenetic consequences. Proc Natl Acad Sci USA 98, 182–187.[CrossRef]
    [Google Scholar]
  20. Ferretti, J. J., McShan, W. M., Ajdic, D. & 20 other authors ( 2001; ). Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc Natl Acad Sci USA 98, 4658–4663.[CrossRef]
    [Google Scholar]
  21. Fischetti, V. ( 2000; ). Surface proteins on gram positive bacteria. In Gram Positive Pathogens , pp. 11-24. Edited by V. A. Fischetti, R. P. Novick, J. J. Ferretti, D. A. Portnoy & J. I. Rood. Washington, DC:American Society for Microbiology.
  22. Geyer, A. & Schmidt, K. H. ( 2000; ). Genetic organisation of the M protein region in human isolates of group C and G streptococci: two types of multigene regulator-like (mgrC) regions. Mol Gen Genet 262, 965-976.[CrossRef]
    [Google Scholar]
  23. Husmann, L. K., Scott, J. R., Lindahl, G. & Stenberg, L. ( 1995; ). Expression of the Arp protein, a member of the M protein family, is not sufficient to inhibit phagocytosis of Streptococcus pyogenes. Infect Immun 63, 345-348.
    [Google Scholar]
  24. Johnson, D., Kaplan, E., Sramek, J., Bicova, R., Havlicek, J., Havlickova, H., Motlova, J. & Kriz, P. (1996). Laboratory Diagnosis of Group A Streptococcal Infections. Geneva: World Health Organization.
  25. Johnston, K. H. & Zabriskie, J. B. ( 1986; ). Purification and partial characterization of the nephritis strain-associated protein from Streptococcus pyogenes, group A. J Exp Med 163, 697-712.[CrossRef]
    [Google Scholar]
  26. Kalia, A., Spratt, B. G., Enright, M. C. & Bessen, D. E. ( 2002; ). Influence of recombination and niche separation on the population genetic structure of the pathogen Streptococcus pyogenes. Infect Immun 70, 1971-1983.[CrossRef]
    [Google Scholar]
  27. Kotarsky, H., Thern, A., Lindahl, G. & Sjobring, U. ( 2000; ). Strain-specific restriction of the antiphagocytic property of group A streptococcal M proteins. Infect Immun 68, 107-112.[CrossRef]
    [Google Scholar]
  28. Lottenberg, R., Broder, C. C., Boyle, M. D. P., Kain, S. J., Schroeder, B. L. & Curtiss, R. I. ( 1992; ). Cloning, sequence analysis, and expression in Escherichia coli of a streptococcal plasmin receptor. J Bacteriol 174, 5204-5210.
    [Google Scholar]
  29. Lyon, W., Gibson, C. & Caparon, M. ( 1998; ). A role for trigger factor and an Rgg-like regulator in the transcription, secretion and processing of the cysteine protease of Streptococcus pyogenes. EMBO J 17, 6263-6275.[CrossRef]
    [Google Scholar]
  30. Malke, H. ( 2000; ). Genetics and pathogenicity factors of group C and G streptococci. In Gram-Positive Pathogens , pp. 163-176. Edited by V. A. Fischetti, R. P. Novick, J. J. Ferretti, D. A. Portnoy & J. I. Rood. Washington, DC:American Society for Microbiology.
  31. Malke, H., Steiner, K., Gase, K. & Frank, C. ( 2000; ). Expression and regulation of the streptokinase gene. Methods 21, 111-124.[CrossRef]
    [Google Scholar]
  32. Maxted, W. R. ( 1980; ). Disease association and geographical distribution of the M types of group A streptococci. In Streptococcal Diseases and the Immune Response , pp. 763-777. Edited by S. E. Read & J. B. Zabriskie. New York:Academic Press.
  33. McIver, K. S. & Scott, J. R. ( 1997; ). Role of mga in growth phase regulation of virulence genes of the group A streptococcus. J Bacteriol 179, 5178-5187.
    [Google Scholar]
  34. Pancholi, V. & Fischetti, V. A. ( 1992; ). A major surface protein of group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176, 415-426.[CrossRef]
    [Google Scholar]
  35. Pancholi, V. & Fischetti, V. A. ( 1998; ). Alpha-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273, 14503-14515.[CrossRef]
    [Google Scholar]
  36. Perez-Casal, J., Price, J. A., Maguin, E. & Scott, J. R. ( 1993; ). An M protein with a single C repeat prevents phagocytosis of Streptococcus pyogenes: use of a temperature-sensitive shuttle vector to deliver homologous sequences to the chromosome of S. pyogenes. Mol Microbiol 8, 809-819.[CrossRef]
    [Google Scholar]
  37. Podbielski, A., Flosdorff, A. & Weber-Heynemann, J. ( 1995; ). The group A streptococcal virR49 gene controls expression of four structural vir regulon genes. Infect Immun 63, 9-20.
    [Google Scholar]
  38. Podbielski, A., Schnitzler, N., Beyhs, P. & Boyle, M. ( 1996; ). M-related protein (Mrp) contributes to group A streptococcal resistance to phagocytosis by human granulocytes. Mol Microbiol 19, 429-441.[CrossRef]
    [Google Scholar]
  39. Podbielski, A., Woischnik, M., Kreikemeyer, B., Bettenbrock, K. & Buttaro, B. A. ( 1999; ). Cysteine protease SpeB expression in group A streptococci is influenced by the nutritional environment but SpeB does not contribute to obtaining essential nutrients. Med Microbiol Immunol 188, 99-109.[CrossRef]
    [Google Scholar]
  40. Raeder, R., Woischnik, M., Podbielski, A. & Boyle, M. D. ( 1998; ). A secreted streptococcal cysteine protease can cleave a surface-expressed M1 protein and alter the immunoglobulin binding properties. Res Microbiol 149, 539-548.[CrossRef]
    [Google Scholar]
  41. Rasmussen, M. & Bjorck, L. ( 2002; ). Proteolysis and its regulation at the surface of Streptococcus pyogenes. Mol Microbiol 43, 537-544.[CrossRef]
    [Google Scholar]
  42. Ringdahl, U., Svensson, M., Wistedt, A., Renné, T., Kellner, R., Müller-Esterl, W. & Sjöbring, U. ( 1998; ). Molecular co-operation between protein PAM and streptokinase for plasmin acquisition by Streptococcus pyogenes. J Biol Chem 273, 6424-6430.[CrossRef]
    [Google Scholar]
  43. Scaramuzzino, D. A., McNiff, J. M. & Bessen, D. E. ( 2000; ). Humanized in vivo model for streptococcal impetigo. Infect Immun 68, 2880-2887.[CrossRef]
    [Google Scholar]
  44. Schrager, H., Alberti, S., Cywes, C., Dougherty, G. & Wessels, M. ( 1998; ). Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A streptococcus to CD44 on human keratinocytes. J Clin Investig 101, 1708-1716.[CrossRef]
    [Google Scholar]
  45. Scott, J. R., Guenther, P. C., Malone, L. M. & Fischetti, V. A. ( 1986; ). Conversion of an M group A streptococcus to M+ by transfer of a plasmid containing an M6 gene. J Exp Med 164, 1641-1651.[CrossRef]
    [Google Scholar]
  46. Sodeinde, O., Subrahmanyam, Y., Stark, K., Quan, T., Bao, Y. & Goguen, J. ( 1992; ). A surface protease and the invasive character of plague. Science 258, 1004-1007.[CrossRef]
    [Google Scholar]
  47. Svensson, M. D., Sjöbring, U. & Bessen, D. E. ( 1999; ). Selective distribution of a high-affinity plasminogen binding site among group A streptococci associated with impetigo. Infect Immun 67, 3915-3920.
    [Google Scholar]
  48. Svensson, M. D., Scaramuzzino, D. A., Sjobring, U., Olsen, A., Frank, C. & Bessen, D. E. ( 2000; ). Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci. Mol Microbiol 38, 242-253.[CrossRef]
    [Google Scholar]
  49. Wannamaker, L. W. ( 1970; ). Differences between streptococcal infections of the throat and of the skin. N Engl J Med 282, 23-31.[CrossRef]
    [Google Scholar]
  50. Yung, D.-L. & Hollingshead, S. K. ( 1996; ). DNA sequencing and gene expression of the emm gene cluster in an M50 group A streptococcus strain virulent for mice. Infect Immun 64, 2193-2200.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/00221287-148-12-3933
Loading
/content/journal/micro/10.1099/00221287-148-12-3933
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