High Frequency Invasion of Mammalian Cells by β Hemolytic Streptococci

  • P. Patrick Cleary
  • David Cue
Part of the Subcellular Biochemistry book series (SCBI, volume 33)


The impact of intracellular invasion on the virulence of S. pyogenes (group A streptococci) and S. agalactiae (group B streptococci) is a rapidly expanding field of investigation. The discovery that members of these species are internalized by a variety of mammalian cells at frequencies equal to or beyond those of the more classical bacterial pathogens has piqued that interest. Investigators are attempting to relate this newfound potential to the pathophysiology of streptococcal disease. This chapter will focus on S. pyogenes, but where possible comparisons will be made to another important streptococcal pathogen, S. agalactiae. Knowledge of bacterial adhesions, is of course, essential for understanding the mechanisms by which bacteria are ingested by non-professional phagocytes; however, studies of S. pyogenes and S. agalactiae adherence mechanisms are a large body of work that is littered with debate and uncertainty and will therefore not be directly addressed here. Reviews of S. pyogenes (Hasty et al., 1992) and S. agalactiae (Tamura and Rubens, 1994) adherence phenomena are cited.


A549 Cell Necrotizing Fasciitis Latex Bead Hemolytic Streptococcus Streptococcal Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akesson, P., Schmidt, K.-H., Cooney, J., and Björck, L., 1994, M1 protein and Protein H: IgGFcand albumin-binding streptococcal surface proteins encoded by adjacent genes, J. Biochem. 300: 877–886.Google Scholar
  2. Burns, E.H., Jr., Lukomski, S., Rurangirwa, J., Podbielski, A., and Musser, J.M., 1998, Genetic inactivation of the extracellular cysteine protease enhances in vitro internalization of group A streptococci by human epithelial and endothelial cells, Microb. Pathog. 24: 333–339.PubMedCrossRefGoogle Scholar
  3. Caparon, M.G., Stephens, D.S., Olsen, A., and Scott, J.R., 1991, Role of M protein in adherence of group A streptococci, Infect. Immun. 59: 1811–1817.PubMedGoogle Scholar
  4. Cedervall, T., Akesson, P., Stenberg, L., Herrmann, A., and Akerstrom, B., 1995, Allosteric and temperature effects on the plasma protein binding by streptococcal M protein family members, Scand. J. Immunol. 42: 433–441.PubMedCrossRefGoogle Scholar
  5. Cleary, PP., LaPenta, D., Vessela, R., Lam, H., and Cue, D., 1998a, A globally disseminated MI subclone of group A streptococcus differs from other subclones by 70kb of prophage DNA and capacity for high frequency intracellular invasion, Infect. Immun. 66: 5592–5597.PubMedGoogle Scholar
  6. Cleary, P.P., McLandsborough, L., Ikedo, L., Cue, D., Krawezak, J., and Lam, H., 1998b, High frequency intracellular infection and erythrogenic toxin A expressions undergo phase variation in M1 group A streptococci, Mol. Microb. 28: 157–167.CrossRefGoogle Scholar
  7. Cleary, P., Kaplan, E.L., Handley, J.P., Wlazlo, A., Kim, M.H., Hauser, A.R., and Schlievert, P.M., 1992, Clonal basis for resurgence of serious streptococcal disease in the 1980’s, Lancet 321: 518–521.CrossRefGoogle Scholar
  8. Cockerill, F.R., MacDonald, K.L., Thompson, R.L., Robertson, E, Kohner, P.C., Besser-Wiek, J., Manahan, J.M., Musser, J.M., Schlievert, P.M., Talbot, J., Frankfort, B., Steckelberg, J.M., Wilson, W.R., and Osterholm, M.T., 1997, An outbreak of invasive group A streptococcal disease associated with high carrige rates of the invasive clone among school-aged children, JAMA 277: 38–43.PubMedCrossRefGoogle Scholar
  9. Courtney, H.S., Dale, J.B., and Hasty, D.L., 1997, Host cell specific adhesins of group A streptococci, Adv. Exp. Med. Biol. 418: 605–606.Google Scholar
  10. Cue, D., Dombek, P.E., Lam, H., and Cleary, P.P., 1998, Serotype Ml Streptococcus pyogenes encodes multiple pathways for entry into human epithelial cells, Infect. Immun. 66: 4593–4601.Google Scholar
  11. Dale, J.B., Washburn, R.G., Marques, M.B., and Wessels, M.R., 1996, Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci, Infect. Immun. 64: 1495–1501.PubMedGoogle Scholar
  12. Dombek, P.E., Cue, D., Sedgewick, J., Lam, H., Ruschkowski, S., Finlay, B.B., and Cleary, P.P., 1998, High frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein mediated invasion and cytoskeletal rearrangements, Mol. Microbiol. 31: in press.Google Scholar
  13. Drevets, D.A., and Campbell, P.A., 1991, Macrophage phagocytosis: use of fluorescence microscopy to distinguish between extracellular and intracellular bacteria, J. Immunol. Methods 142: 31–38.PubMedCrossRefGoogle Scholar
  14. Duensing, T.D., and van Putten, J.P., 1997, Vitronectin mediates internalization of Neisseria gonorrhoeae by Chinese hamster ovary cells, Infect. Immun. 65: 964–970.Google Scholar
  15. Ewanowich, C.A., Sherburne, R.K., Man, S.F., and Peppier, M.S., 1989, Bordetella parapertussis invasion of HeLa 229 cells and human respiratory epithelial cells in primary culture, Infect. Immun. 57:1240–1247 .Google Scholar
  16. Falcioni, R., Cimino, L., Gentileschi, M.P., D’Agnano, I., Zupi, G., Kennel, S.J., and Sacchi, A., 1994, Expression of 131,133,134, and 135 integrins by human lung carcinoma cells of different histotypes, Exp. Cell Res. 210: 113–122.PubMedCrossRefGoogle Scholar
  17. Finlay, B.B., and Falkow, S., 1997, Common themes in microbial pathogenicity revisited, MicrobioL Molec. Biol. Rev. 61:136–169.Google Scholar
  18. Fischetti, V.A., 1989, Streptococcal M protein: molecular design and biological behavior, Clin. Microbiol. Rev. 2:285–314.Google Scholar
  19. Fluckiger, U., Jones, K.F., and Fischetti, V.A., 1998, Immunoglobulins to group A streptococcal surface molecules decrease adherence to and invasion of human pharyngeal cells, Infect. immun. 66:974–979.Google Scholar
  20. Francis, C.L., Starbach, M.M., and Falkow, S., 1992, Morphological and cytoskeletal changes in epithelial cells occur immediately upon interaction of Salmonella typhimurium grown under low-oxygen conditions, Mol. Microbiol. 6: 3077–3087.PubMedCrossRefGoogle Scholar
  21. Frick, I.-M., Crossin, K.L., Edelman, G.M., and Björck, L., 1995, Protein H- a bacterial surface protein with affinity for both immunoglobulin and fibronectin type III domains, J. EMBO 14: 1674–1679.Google Scholar
  22. Garcia-del Portillo, E, and Finlay, B.B., 1995, Targeting of Salmonella typhimurium to vesicles containing lysosomal membrane glycoproteins bypasses compartments with mannose 6-phosphate receptors, J. Cell Biol. 129:81–97.Google Scholar
  23. Gomez-Duarte, O.G., Dehio, M., Guzman, C.A., Chhatwal, G.S., Dehio, C., and Meyer, T.F., 1997, Binding of vitronectin to Opa-expressing Neisseria gonorrhoeae mediates invasion of HeLa cells, Infect. Immun. 65: 3857–3866.PubMedGoogle Scholar
  24. Greco, R., De Martino, L., Donnarumma, G., Conte, M.P., Seganti, L., and Valenti, R, 1995, Invasion of cultured human cells by Streptococcus pyogenes, Res. Microbiol. 146: 5551–5560.CrossRefGoogle Scholar
  25. Greco, R., von Hunolstein, C., Orefici, G., Donnarumma, G., Nicoletti, M., and Valenti, R, 1998, Protein M and fibronectin-binding proteins are not sufficient to promote internalization of group A streptococci into HeLa cells, International J. Immunopathology and Pharmacology In press.Google Scholar
  26. Hanski, E., and Caparon, M., 1992, Protein F, a fibronectin-binding protein, is an adhesin of the group A streptococcus Streptococcus pyogenes, Proc. Natl. Acad. Sci. USA 89: 6172–6176.PubMedCrossRefGoogle Scholar
  27. Horwitz, M.A., 1994, Phagocytosis by the Legionnaires’ disease bacterium (Legionella pneumophilia) occurs by a novel mechanism: engulfment within a pseudopod coil, Cell 36: 27–33.CrossRefGoogle Scholar
  28. Hulse, M.L., Smith, S., Chi, E.Y., Pham, A., and Rubens, C.E., 1993, Effect of type III group B streptococcae capsular polysaccharide on invasion of respiratory epithelial cells, Infect. Immun. 61: 4835–4841.PubMedGoogle Scholar
  29. Hynes, R.O., 1992, Integrins: versatility, modulation, and signaling in cell adhesion, Cell 69: 11–25.PubMedCrossRefGoogle Scholar
  30. Isberg, R.R., and Leong, J.M., 1990, Multiple 131 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells, Cell 60: 861–871.PubMedCrossRefGoogle Scholar
  31. Jadoun, J., Ozeri, V., Burstein, E., Skutelsky, E., Hanski, E., and Sela, S., 1998, Protein Fl is required for efficient entry of Streptococcus pyogenes into epithelial cells, J. Infect. Dis. 178: 147–158.PubMedCrossRefGoogle Scholar
  32. Jaffe, J., Natanson-Yaron, S., Caparon, M.G., and Hanski, E., 1996, Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains, Mol. Microbiol. 21: 373–384.PubMedCrossRefGoogle Scholar
  33. Ji, Y., Carlson, B., Kondagunta, A., and Cleary, P., 1997, Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization by groupA Streptococcus, Infect. Immun. 65: 2080–2087.PubMedGoogle Scholar
  34. Ullman, J., and Kihlstrom, E., 1997, Penetration of group B streptococci through polarized Madin-Darby canine kidney cells, Pediatric Research 42: 799–804.CrossRefGoogle Scholar
  35. Katerov, V., Andreev, A., Schalen, C., and Totolian, A.A., 1998, Protein F, a fibronectin-binding protein of Streptococcus pyogenes, also binds human fibrinogen: isolation of the protein and mapping of the binding region, Microbiology 14: 119–126.CrossRefGoogle Scholar
  36. Kuroda, K., Brown, E.J., Telle, W.B., Russell, D.G., and Ratliff, T.L., 1993, Characterization of the internalization of bacillus Calmette-Guerin by human bladder tumor cells, J. Clin. Invest. 91: 69–76.PubMedCrossRefGoogle Scholar
  37. LaPenta, D., Rubens, C., Chi, E., and Cleary, P.P., 1994, Group A steptococci efficiently invade human respiratory epithelial cells, Proc. Natl. Acad. Sci, USA 91: 12115–12119.CrossRefGoogle Scholar
  38. Mengaud, J., Ohayon, H., Gounon, R, Mege, R.-M., and Cossart, R, 1996, E-cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells, Cell 84: 923–932.PubMedCrossRefGoogle Scholar
  39. Molinara, G., and Chhatwal, G.S., 1998, Invasion and survival of Streptococcus pyogenes in eukaryotic cells correlates with the source of the clinical isolates, J. Infect. Dis. 177: 1600–1607.CrossRefGoogle Scholar
  40. Molinari, G., Talay, S.R., Valentin-Weigand, P., Rohde, M., and Chhatwal, G.S., 1997, The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells, Infect. Immun. 65: 1357–1363.PubMedGoogle Scholar
  41. Musser, J.M., Kapur, V., Szeto, J., Pan, X., Swanson, D.S., and Martin, D.R., 1995, Genetic diversity and relationships among Streptococcus pyogenes strains expressing serotype M1 protein: recent intercontinental spread of a subclone causing episodes of invasive disease, Infect. Immun. 63: 994–1003.PubMedGoogle Scholar
  42. Nath, S.K., 1989, Invasion of HeLa cells by 0-hemolytic group G streptococci, Can. J. Microbiol. 35: 515–517.PubMedCrossRefGoogle Scholar
  43. Neeman, R., Keller, N., Barzilai, A., Korenman, Z., and Sela, S., 1998, Prevalence of the internalization-associated gene, prtFl, among persisting group A streptococcus strains isolated from asymptomatic carriers, Lancet 352: 1974–1977.PubMedCrossRefGoogle Scholar
  44. Nilson, B.H., Frick, I.M., Akesson, P., Forsen, S., Bjorck, L., Akerstrom, B., and Wikstrom, M., 1995, Structure and stability of protein H and the Ml protein from Streptococcus pyogenes. Implications for other surface proteins of gram-positive bacteria, Biochemistry 34: 13688–13698.PubMedCrossRefGoogle Scholar
  45. Nizet, V., Kim, K.S., Stins, M., Jonas, M., Chi, E.Y., Nguyen, D., and Rubens, C.E., 1997, Invasion of brain microvascular endothelial cells by group B streptococci, Infect. Immun. 65: 5074–5081.PubMedGoogle Scholar
  46. Oelschlaeger, T.A., Barrett, T.J., and Kopecko, K.J., 1994, Some structures and processes of human epithelial cells involved in uptake of enterohemorrhagic Escherichia coli 0157:H7 strains, Infect. Immun. 62: 5142–5150.PubMedGoogle Scholar
  47. Okada, N., Pentland, A.P., Falk, P., and Caparon, M.G., 1994, M protein and protein F act as important determinants of cell-specific tropism of Streptococcus pyogenes in skin tissue, J. Clin. Invest. 94: 965–977.PubMedCrossRefGoogle Scholar
  48. Okada, N., Liszewski, M.K., Atkinson, J.P., and Caparon, M., 1995, Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus, Proc. Natl. Acad. Sci. USA 92: 2489–2493.PubMedCrossRefGoogle Scholar
  49. Okada, N., Watarai, M., Ozeri, V., Hanski, E., Caparon, M., and Sasakawa, C., 1997, A matrix form of fibronectin mediates enhanced binding of Streptococcus pyogenes to host tissue, J. Biol. Chem. 272: 26978–26984.PubMedCrossRefGoogle Scholar
  50. Österlund, A., Popa, R., Nikkila, T., Scheynius, A., and Engstrand, L., 1997, Intracellular reservoir of Streptococcus pyogenes in vivo: a possible explanation for recurrent pharyngotonsillitis, Laryngoscope 107: 640–647.PubMedCrossRefGoogle Scholar
  51. Österlund, A., and Engstrand, L., 1995, Intracellular penetration and survival of Streptococcus pygenes in respiratory epithelial cells in vitro, Acta Otolaryngol 115: 685–688.PubMedCrossRefGoogle Scholar
  52. Ozeri, V., Rosenshine, I., Mosher, D.F., Fassler, R., and Hanski, E., 1998, Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein Fl, Mol. Microbiol. 30: 625–637.PubMedCrossRefGoogle Scholar
  53. Ozeri, V., Tovi, A., Burstein, I., Natanson-Yaron, S., Caparon, M.G., Yamada, K.M., Akiyama, S.K., Vlodaysky, I., and Hanski, E., 1996, A two-domain mechanism for group A streptococcal adherence through protein F to the extracellular matrix, J. EMBO 15: 989–998.Google Scholar
  54. Patti, J.M., Allen, B.L., McGavin, M.J., and Hook, M., 1994, MSCRAMM-mediated adherence of microorganisms to host tissues, Annu. Rev. Microbiol. 48: 585–617.PubMedCrossRefGoogle Scholar
  55. Pincus, S.H., Cole, R.L., Wessels, M.R., Corwin, M.D., Kamanga-Sollo, E., Hayes, S.E, and Cieplak, W., Jr., Swanson, J., 1992, Group B streptococcal opacity variants, J. Bacteriol. 174: 3739–3749.Google Scholar
  56. Rambukkana, A., Salzer, J.L., Yurchenco, P.D., and TLomanen, E.I., 1997, Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-a2 chain, Cell 88: 811–821.PubMedCrossRefGoogle Scholar
  57. Rubens, C.E., Smith, S., Hulse, M., and Chi, E.Y., 1992, Respiratory epithelial cells invasion by group B streptococci, Infect. Immun. 60: 5157–5163.PubMedGoogle Scholar
  58. Rubens, C.E., Raff, H.V., Jackson, J.C., and Chi, E.Y., 1991, Pathophysiology and histopathology of group B streptococcal sepsis in Macaca hemestrina primates induced after intra-amniotic inoculation: evidence for bacterial cellular invasion, J. Infect. Dis. 164: 320–333.PubMedCrossRefGoogle Scholar
  59. Schlievert, P.M., Assimacopoulos, A.P., and Cleary, P.P., 1996, Severe invasive group A streptococcal disease: clinical description and mechanisms of pathogenesis. J. Lab. Clin. Med. 127: 13–22.PubMedCrossRefGoogle Scholar
  60. Schmidt, K.-H., Mann, K., Cooney, J., and Kohler, W., 1993, Multiple binding of type 3 streptococcal M protein to human fibrinogen, albumin and fibronectin, FEMS Immunol. Med. Microbiol. 7: 135–144.PubMedCrossRefGoogle Scholar
  61. Schorey, J.S., Li, Q., McCourt, D.W., Bong-Mastek, M., Clark-Curtiss, J.E., Ratliff, T.L., and Brown, E.J., 1995, A Mycobacterium leprae gene encoding a fibronectin binding protein is used for efficient invasion of epithelial cells and Schwann cells, Infect. Immun. 63: 2652–2657.PubMedGoogle Scholar
  62. Schrager, H.M., Rheinwald, J.G., and Wessels, M.R., 1996, Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes invasive skin infection, J. Clin. Invest. 98: 1954–1958.PubMedCrossRefGoogle Scholar
  63. Schwartz, M.A., Schaller, M.D., and Ginsberg, M., 1995, Integrins: emerging paradigms of signal transduction, Annu. Rev. Cell Dev. Biol. 11: 549–559.PubMedCrossRefGoogle Scholar
  64. Schwarzbauer, J.E., 1991, Fibronectin: from gene to protein, Curr. Opin. Cell Biol. 3:786–791.PubMedCrossRefGoogle Scholar
  65. Sellin, M., Hakausson, S., and Norgren, M., 1995, Phase-shift of polysaccharide capsule expression in group B streptococci, type III, Microb. Pathog. 18: 401–415.PubMedCrossRefGoogle Scholar
  66. Stevens, D.L., Tanner, M.H., Winship, J., Swarts, R., Ries, K., Schlievert, P., and Kapland, E., 1989, Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A, New Engl. J. Med. 321: 1–7.PubMedCrossRefGoogle Scholar
  67. St. Genie, J.W., III, and Falkow, S., 1990, Haemophilus influenzae adheres to and enters cultured human epithelial cells, Infect. Immun. 58: 4036–4044.Google Scholar
  68. Switalski, L.M., Speziale, P., Hook, M., Wadstrom, T., and Timpl, R., 1984, Binding of Streptococcus pyogenes to laminin, J. Biol. Chem. 259: 3734–3738.PubMedGoogle Scholar
  69. Talay, S.R., Valentin-Weigand, P., Timmis, K.N., and Chhatwal, G.S., 1994, Domain structure and conserved epitopes of Sfb protein, the fibronectin-binding adhesin of Streptococcus pyogenes, Mol. Microbiol. 13: 531–539.PubMedCrossRefGoogle Scholar
  70. Tamura, G.S., and Rubens, C.E., 1994, Pathogenesis of group B streptococcal infections, Curr. Opin. Inf. Dis. 7: 317–322.CrossRefGoogle Scholar
  71. Timpl, R., and Brown, J.C., 1994, The laminins, Matrix Biol. 14: 275–281.PubMedCrossRefGoogle Scholar
  72. Tsai, RI, Kuo, C.F., Lin, K.Y., Lin, Y.S., Lei, H.Y., Chen, F.F., Wang, J.R., and Wu, J.J., 1998, Effect of group A streptococcal cysteine protease on invasion of epithelial cells, Infect. Immun. 66: 1460–1466.PubMedGoogle Scholar
  73. Valentin-Weigand, P., Benkel, P., Rohde, M., and Chhatwal, G.S., 1996, Entry and intracellular survival of group B streptococci in J774 macrophages, Infect. Immun. 64: 2467–2473.Google Scholar
  74. Valentin-Weigand, P., and Chhatwal, G.S., 1995, Correlation of epithelial cell invasiveness of group B streptococci with clinical source of isolation, Microb. Pathog. 19: 83–91.PubMedCrossRefGoogle Scholar
  75. Valentin-Weigand, P., Jungnitz, H., Zock, A., Rohde, M., and Chhatwal, G.S., 1997, Characterization of group B streptococcal invasion in HEp-2 epithelial cells, FEMS Microb. Letts. 147: 69–74.CrossRefGoogle Scholar
  76. van Nhieu, G.T., and Isberg, R.R., 1991, The Yersinia pseudotuberculosis invasin protein and human fibronectin bind to mutually exclusive sites on the a5131 integrin receptor, J. Biol. Chem. 266: 24367–24375.PubMedGoogle Scholar
  77. van Putten, J.P., Duensing, T.D., and Cole, R.L., 1998, Entry of OpaA+ gonococci into HEp-2 cells requires concerted action of glycosaminoglycans, fibronectin and integrin receptors, Mol. Microbiol. 29: 369–379.PubMedCrossRefGoogle Scholar
  78. Winram, S.B., Jonas, M., Chi, E., and Rubens, C.E., 1998, Characterization of group B streptococcal invasion into human chorion and amnion epithelial cells in vitro, Infect. Immun. 66: 4932–4941.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • P. Patrick Cleary
    • 1
  • David Cue
    • 1
  1. 1.Department of MicrobiologyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations