Microtubule Dependent Invasion Pathways of Bacteria

  • Tobias A. Oelschlaeger
  • Dennis J. Kopecko
Part of the Subcellular Biochemistry book series (SCBI, volume 33)


Bacterial pathogens have evolved mechanisms to resist standard host defenses and to subvert normal host machinery in order to initiate disease. Invasive bacterial pathogens are now known to interact, via biochemical crosstalk, with the host, stimulating a signal transduction cascade(s) that results in host cytoskeletal rearrangements that lead to internalization of the pathogen. Until about five years ago, virtually all bacterial uptake pathways involved the exclusive requirement for host microfilaments (MFs). Since then, internalization into host cells for several bacterial genera has been reported to require microtubules (MTs) alone or together with MFs. Despite striking differences in the host cell cytoskeletal requirements for invasion, all bacterial uptake pathways have followed a common mechanistic scheme. In this general scheme, a bacterial “invasion effector ligand(s)” interacts with an eukaryotic receptor to induce a signal transduction cascade leading ultimately to the cytoskeletal rearrangements necessary for internalization. Of special interest are the receptors and intermediary host molecules which transduce the initial bacterial signal through the host cell thereby activating cytoskeletal changes and uptake of the bacterium, intracellular survival and movement of the bacterium, and sometimes exocytic release of the pathogen. In contrast to the many plasma membrane receptors with well-documented connection to cytoskeletal microfilaments, there are only a few examples of known membrane components which are connected with the microtubular cytoskeleton.


Chlamydia Trachomatis Neisseria Gonorrhoeae Bacterial Invasion Mycobacterium Bovis Uptake Pathway 
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  1. Amin, K., Beillevaire, D., Mahmoud, E., Hammar, L., Mardh, P.H., and Froman, G., 1995, Binding of Galanthus nivalis lectin to Chlamydia trachomatis and inhibition of in vitro infection, APMIS 103: 714–720.PubMedCrossRefGoogle Scholar
  2. Andreev, J., Borovsky, Z., Rosenshine, I., and Rottem, S., 1995, Invasion of HeLa cells by Mycoplasma penetrans and the induction of tyrosine phosphorylation of a 145 kDa host cell protein, FEMS Microbiol. Lett. 132: 189–194.PubMedCrossRefGoogle Scholar
  3. Baorto, D.M., Gao, Z., Malaviya, R., Dustin, M.L., van der Merwe, A., Lublin, D.M., and Abraham, S.N., 1997, Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic, Nature 389: 636–639.PubMedCrossRefGoogle Scholar
  4. Bermudez, L.E., and Goodman, J., 1996, Mycobacterium tuberculosis invades and replicates within type II alveolar cells, Infect. Immun. 64: 1400–1406.Google Scholar
  5. Birkelund, S., Johnsen, H., and Christiansen, G., 1994, Chlamydia trachomatis serovar L2 induces protein tyrosine phosphorylation during uptake by HeLa cells, Infect. Immun. 62: 4900–4908.Google Scholar
  6. Borovsky, Z., Tarshis, M., Zhang, P., and Rottem, S., 1998, Protein kinase C activation and vacuolation in HeLa cells invaded by Mycoplasma penetrans, J. Med. Microbiol. 47: 915–922.PubMedCrossRefGoogle Scholar
  7. Bozue, J.A., and Johnson, W., 1996, Interaction of Legionella pneumophila with Acanthamoeba castellanii: uptake by coiling phagocytosis and inhibition of phagosome-lysosome fusion, Infect. Immun. 64: 668–673.PubMedGoogle Scholar
  8. Buchwalow, I.B., Brich, M., and Kaufmann, S.H., 1997, Signal transduction and phagosome biogenesis in human macrophages during phagocytosis of Mycobacterium bovis BCG, Acta. Histochem. 99: 63–70.PubMedCrossRefGoogle Scholar
  9. Clausen, J.D., Christiansen, G., Holst, H.U., and Birkelund, S., 1997, Chlamydia trachomatis utilizes the host cell microtubule network during early events of infection, Mol. Microbiol. 25: 441–449.Google Scholar
  10. Donnenberg, M.S., Donohue-Rolfe, A., and Keusch, G.T., 1990, A comparison of Hep-2 cell invasion by enteropathogenic and enteroinvasive Escherichia coli, FEMS Microbiol. Leu. 69: 83–86.CrossRefGoogle Scholar
  11. Duensing, T.D., and van Putten, J.P.M., 1997, Vitronectin mediates internalization of Neisseria gonorrhoeae by chinese hamster ovary cells, Infect. Immun. 65: 964–970.PubMedGoogle Scholar
  12. Elsinghorst, E.A., 1994, Measurement of invasion by gentamicin resistance, Methods. Enzymol. 236: 405–420.PubMedCrossRefGoogle Scholar
  13. Foubister, V., Rosenshine, I., and Finaly, B.B., 1994, A diarrheal pathogen, enteropathogenic Escherichia coli (EPEC), triggers a flux of inositol phosphates in infected epithelial cells, J. Exp. Med. 179: 993–998.PubMedCrossRefGoogle Scholar
  14. Fumagalli, O., Tall, B.D., Schipper, C., and Oelschlaeger, T.A., 1997, N-glycosylated proteins are involved in efficient internalization of Klebsiella pneumoniae by cultured human epithelial cells, Infect. Immun. 65: 4445–4451.PubMedGoogle Scholar
  15. Grassme, H.U., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., and Meyer, T.F., 1997, Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells, Cell 91: 605–615.PubMedCrossRefGoogle Scholar
  16. Grassme, H.U., Ireland, R.M., and van Putten, J.P., Gonococcal opacity protein promotes bacterial entry-associated rearrangement of the epithelial cell actin cytoskeleton, Infect. Immun. 64: 1621–1630.Google Scholar
  17. Gray-Owen, S.D., Dehio, C., Haude, A., Grunert, F, and Meyer, T.F., 1997, CD66 carcinoembryonic antigens mediate interaction between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes, EMBO J. 16: 3435–3445.PubMedCrossRefGoogle Scholar
  18. Goluszko, P., Popov, V., Selvarangan, R., Novicki, S., Pham, T., and Nowicki, B.J.,1997, Dr fimbriae operon of uropathogenic Escherichia coli mediate microtubule-dependent invasion to the HeLa epithelial cell line, J. Infect. Dis. 176: 158–167.Google Scholar
  19. Guzman, C.A., Rhode, M., Chakraborty, T., Domann, E., Hudel, M., Wehland, J., and Timmis, K.N., 1995, Interaction of Listeria monocytogenes with mouse dendritic cells, Infect. Immun. 63: 3665–3673.PubMedGoogle Scholar
  20. Guzman, C.A., Rhode, M., and Timmis, K.N., 1994, Mechanisms involved in uptake of Bordetella brbnchiseptica by mouse dentritic cells, Infect. Immun. 62: 5538–5544.PubMedGoogle Scholar
  21. Hart, P.D., Young, M.R., Gordon, A.H., and Sullivan, K.H., 1987, Inhibition of phagosomelysosome fusion in macrophages by certain mycobacteria can be explained by inhibition of lysosomal movements observed after phagocytosis, J. Exp. Med. 166: 933–946.PubMedCrossRefGoogle Scholar
  22. Horwitz, M.A., 1983, The legionaires’ disease bacterium (Legionella phneumophila) inhibits phagosome-lysosome fusion in human monocytes, J. Exp. Med. 158: 2108–2126.PubMedCrossRefGoogle Scholar
  23. Hueck, C.J., 1998, Type III secretion systems in bacterial pathogens of animals and plants, Microbiol. Mol. Biol. Rev. 62: 379–433.PubMedGoogle Scholar
  24. Isberg, R.R., and Leong, J.M., 1990, Multiple bl chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells, Cell 60: 861–871.PubMedCrossRefGoogle Scholar
  25. Itzutsu, K.T., Belton, C.M., Chan, A., Fatherazi, S., Kanter, J.P., Park, Y., and Lamont, R.J., 1996, Involvement of calcium in interactions between gingival epithelial cells and Porphyromonas gingivalis, FEMS Microbiol. Leu. 144: 145–150.CrossRefGoogle Scholar
  26. Jouve, M., Garcia, M.-I., Courcoux, P., Labigne, A., Gounon, P., and Bouguenec, C.L., 1997, Adhesion to and invasion of HeLa cells by pathogenic Escherichia coli carrying the afa-3 gene cluster are mediated by the AfaE and AfaD proteins, respectively, Infect. Immun. 65: 4082–4089.PubMedGoogle Scholar
  27. Kenny, B., 1999, Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleation activity and is preceded by additional host modifications, Mol. Microbiol. 31: 1229–1241.PubMedCrossRefGoogle Scholar
  28. Kenny, B., and Finlay, B.B., 1997a, Intimin-dependent binding of enteropathogenic Escherichia coli to host cells triggers novel signaling events, including tyrosine phosphorylation of phospholipase C-71, Infect. Immun. 65: 2528–2536.PubMedGoogle Scholar
  29. Kenny, B., DeVinney, R., Stein, M., Remscheid, D.J., Frey, E.A., and Finlay, B.B., 19976, Enteropathogenic E. coli (EPEC) transfer its receptor for intimate adherence into mammalian cells, Cell 91: 511–520.Google Scholar
  30. Kirsch, J., Langosch, D., Prior, P., Littauer, U.Z., Schmitt, B., and Betz, H., 1991, The 93 kDa glycine receptor-associated protein binds to tubulin, J. Biol. Chem. 266: 22242–22245.PubMedGoogle Scholar
  31. Kishi, F, Yoshida, T., and Aiso, S., 1996, Location of NRAMPI molecule on the plasma membrane and its association with microtubules, Mol. Immunol. 33: 1241–1246.PubMedCrossRefGoogle Scholar
  32. Kuhn, M., 1998, The microtubule depolymerizing drugs nocodazole and colchicine inhibit the uptake of Listeria monocytogenes by P388D1 macrophages, FEMS Microbiol. Lett. 160: 87–90.PubMedCrossRefGoogle Scholar
  33. 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
  34. Lamont, R.J., Chan, A., Belton, C.M., Izutzu, K.T., Vasel, D., and Weinberg, A., 1995, Porphyromonas gingivalis invasion of gingival epithelial cells, Infect. Immun. 63: 3878–3885.Google Scholar
  35. Leininger, E., Ewanowich, C.A., Bhargava, A., Peppier, M.S., Kenimer, J.G., and Brennan, M.J., 1992, Comparative roles of the Arg-Gly-Asp sequence present in the Bordetella pertussis adhesins pertactin and filamentous hemagglutinin, Infect. Immun. 60: 2380–2385.PubMedGoogle Scholar
  36. Madianos, P.N., Papapanou, P.N., Nannmark, U., Dahlen, G., and Sandros, J., 1996, Porphyromonas gingivalis FDC381 multiplies and persists within human oral epithelial cells in vitro, Infect. Immun. 64: 660–664.Google Scholar
  37. Maruta, K., Ogawa, M., Miyamoto, H., Izu, K., and Yoshida, S.I., 1998, Entry and intracellular localization of Legionela dumoffii in Vero cells, Mircob. Pathog. 24: 65–73.CrossRefGoogle Scholar
  38. Meier, C., Oelschlaeger, T.A., Merkert, H., Korhonen, T.K., and Hacker, J., 1996, Ability of the newborn meningitis isolate Escherichia coli IHE3034 (O18:K1:H7) to invade epithelial and endothelial cells, Infect. Immun. 64: 2391–2399.Google Scholar
  39. Moon, H.W., Whipp, S.C., Argenzio, R.A., Levine, M.M., and Gianella, R.A., 1983, Attaching and effacing activities of rabbit and human enteropathogenic Escherichia coli in pig and rabbit intestines, Infect. Immun. 41: 1340–1351.PubMedGoogle Scholar
  40. Nathke, I.S., Adams, C.L., Polakis, P., Sellin, J.H., and Nelson, W.J., 1996, The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration, J. Cell. Biol. 134: 165–179.PubMedCrossRefGoogle Scholar
  41. Nowicki, B., Hart, A., Coyne, K.E., Lublin, D.M., and Nowicki, S., 1993, Short consensus repeat-3 domain of recombinant decay-accelerating factor is recognized by Escherichia coli recombinant Dr adhesin in a model of cell-cell interaction, J. Exp. Med. 178: 2115–2121.PubMedCrossRefGoogle Scholar
  42. Oelschlaeger, T.A., and Tall, B.D., 1997, Invasion of cultured human epithelial cells by Klebsiella pneumoniae isolated from the urinary tract, Infect. Immun. 65: 2950–2958.PubMedGoogle Scholar
  43. Oelschlaeger, T.A., Barrett, T.J., and Kopecko, D.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
  44. Oelschlaeger, T. A., Guerry, P., and Kopecko, D.J., 1993, Unusual microtubule-dependent endocytosis mechanisms triggered by Campylobacter jejuni and Citrobacter freundii, Proc. Natl. Acad. Sci. USA 90: 6884–6888.PubMedCrossRefGoogle Scholar
  45. Ooij, C., Apodaca, G., and Engel, J., 1997, Characterization of the Chlamydia trachomatis vacuole and its interaction with the host endocytic pathway in HeLa cells, Infect. Immun. 65: 758–766.PubMedGoogle Scholar
  46. Pham, T.Q., Góluszko, P., Popov, V., Nowicki, S., and Nowicki, B.J., 1997, Molecular cloning and characterization of Dr-II, a nonfimbrial adhesin-I-like adhesin isolated from gestational pyelonephritis-associated Escherichia coli that binds to decay-accelerating factor, Infect. Immun. 65: 4309–4318.PubMedGoogle Scholar
  47. Prasadarao, N.V., Wass, C.A., and Kim, K.S., 1996, Endothelial cell GIcNAcß1–4GIcNAc epitopes for outer membrane protein A enhances traversal of Escherichia coli actross the blood brain barrier, Infect. Immun. 64: 154–160.PubMedGoogle Scholar
  48. Raulston, J.E., Davis, C.H., Schmiel, D.H., Morgan, M.W., and Wyrick, P.B., 1993, Molecular characterizationand outermembrane association of a Chlamydia trachomatis protein related to the hsp70 family of proteins, J. Biol. Chem. 268: 23139–23147.PubMedGoogle Scholar
  49. Ravindra, R., 1997, Is signal transduction modulated by an interaction between heterotrimeric G-proteins and tubulin?, Endocrine 7: 127–143.PubMedCrossRefGoogle Scholar
  50. Russel, R.G., O’Donnoghue, M., Blake, D.C., Zulty, J., and DeTolla, L.J., 1993, Early colonic damage and invasion of Campylobacter jejuni in experimentally challenged infant Macaca mulatta, J. Infect. Dis. 168: 210–215.CrossRefGoogle Scholar
  51. Rikihisa, Y., Zhang, Y., and Park, J., 1995, Role of Ca2+ and calmodulin in ehrlichial infection in macrophages, Infect. Immun. 63: 2310–2316.PubMedGoogle Scholar
  52. Sandros, J., Papapanou, P., and Dahlen, G., 1993, Porphyromonas gingivalis invades oral epithelial cells in vitro, J. Periodontal Res. 28: 219–226.CrossRefGoogle Scholar
  53. Scalettsky, I.C.A., Gatti, M.S.V., da Silveira, J.F., DeLuca, I.M.S., Freymuller, E., and Travassos, L.R., 1995, Plasmid coding for drug resistance and invasion of: epithelial cells in enteropathogenic Escherichia coli 0111:H-, Microb. Pathog. 18: 387–399.CrossRefGoogle Scholar
  54. Schipper, H., Krohne, G.F., and Gross, R., 1994, Epithelial cell invasion and survival of Bordetella bronchiseptica, Infect. Immun. 62: 3008–3011.PubMedGoogle Scholar
  55. Staley, T.E., Jones, E.W., and Corley, L.D., 1969, Attachment and penetration of Escherichia coli into intestinal epithelium of the ileum in newborn pigs. Am. J. Pathol. 56: 371–392.PubMedGoogle Scholar
  56. St Geme, III, J.W., de la Morena, M.L., and Falkow, S., 1994, A Haemophilus influenzae IgA protease-like protein promotes intimate interaction with human epithelial cells, Mol. Microbiol. 14: 217–233.Google Scholar
  57. Sturgill-Koszycki, S., Schlesinger, P.H., Chakraborty, P., Haddix, P.L., Collins, H.L., Fok, A.K., Allen, R.D., Gluck, S.L., Heuser, J., and Russel, D.G., 1994, Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase, Science 263: 678–681.PubMedCrossRefGoogle Scholar
  58. Subtil, A., and Dautry-Varsat, A., 1997, Microtubule depolymerization inhibits clathrin coated-pit internalization in non-adherent cell lines while interleukin 2 endocytosis is not affected; J. Cell Sci. 110: 2441–2447.PubMedGoogle Scholar
  59. Swanson, A.F., and Kuo, C.-C., 1994, Binding of the glycan of the major outer membrane protein of Chlamydia trachomatis to HeLa cells, Infect. Immun. 62: 24–28.PubMedGoogle Scholar
  60. Tang, P., Sutherland, C.L., Gold, M.R., and Finlay, B.B., 1998, Listeria monocytogenes invasion of epithelial cells requires the MEK-1/ERK-2 mitogen-activated protein kinase pathway, Infect. Immun. 66: 1106–1112.Google Scholar
  61. Tran Van Nhieu, G., and Isberg, R.R., 1993, Bacterial internalization mediated by ß1 chain integrins is determinend by ligand affinity and receptor density, EMBO J. 12: 1887–1895.Google Scholar
  62. Tzipori, S., Robins-Browne, R.M., Gonis, G., Hayes, J., Withers, M., and McCartney E., 1985, Enteropathogenic Escherichia coli enteritis: evaluation of the gnotobiotic piglet as a model of human infection, Gut 26: 570–578.PubMedCrossRefGoogle Scholar
  63. Uhlsen, M.H., and Rollo, J.L., 1980, Pathogenesis of Escherichia coli gastroenteritis in man—another mechanism, N. Engl. J. Med. 302: 99–101.CrossRefGoogle Scholar
  64. Van de Water, L., Destree, A.T., and Hynes, R.O., 1983, Fibronectin binds to some bacteria but does not promote their uptake by phagocytic cells, Science 220: 201–204.PubMedCrossRefGoogle Scholar
  65. Van Spreeuwel, J.P., Duursma, G.C., Meijer, C.J., Bax, R., Rosekrans, P.C., and Lindeman, J., 1985, Campylobacter colitis: histological immunohistochemical and ultrastructural findings, Gut 26: 945–951.PubMedCrossRefGoogle Scholar
  66. Virji, M., Käythy, H., Ferguson, D.J.P., Alexandrescu, C., and Moxon, E.R., 1992, Interactions of Hämophilus influenzae with human endothelial cells in vitro, J. Infect. Dis. 165 (suppl 1): S115 - S116.PubMedCrossRefGoogle Scholar
  67. Virji, M., Makepeace, K., and Moxon, E.R., 1994, Distinct mechanisms of interactions of Opcexpressing meningococci at apical and basolateral surfaces of human endothelial cells; the role of integrins in apical interactions, Mol. Microbiol. 14: 173–184.PubMedCrossRefGoogle Scholar
  68. Virji, M., Makepeace, K., Ferguson, D.J., and Watt, S.M., 1996a, Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic neisseriae, Mol. Microbiol. 22: 941–950.PubMedCrossRefGoogle Scholar
  69. Virji, M., Makepeace, K., Ferguson, D.J., and Watt, S.M., 1996b, The N-domain of the human CD66a adhesion molecule is a target for Opa proteins of Neisseria meningitides and Neisseria gonorrhoeae, Mol. Microbiol. 22: 929–939.PubMedCrossRefGoogle Scholar
  70. Wang, H., Bedford, F.K., Brandon, N.J., Moss, S.J., and Olsen, R.W., 1999, GABAA-receptor- associated protein links GABAA receptors and the cytoskeleton, Nature 397: 69–72.PubMedCrossRefGoogle Scholar
  71. Weinberg, A., Belton, C.M., Park, Y., and Lamont, R.J., 1997, Role of fimbriae in Porphy- romonas gingivalis invasion of gingival epithelial cells, Infect. Immun. 65: 313–316.PubMedGoogle Scholar
  72. Weikert, L.F., Edwards, K., Chroneos, Z.C., Hager, C., Hoffman, L., and Shepherd, V.L., 1997, SP-A enhances uptake of bacillus Calmette-Guerin by macrophages through a specific SP-A receptor, Am. J. Physiol. 272 (5Pt1): L989 - L995.PubMedGoogle Scholar
  73. Wells, M.Y., and Rikihisa, Y., 1988, Lack of lysosomal fusion with phagosomes containing Ehrlichia risticii in P388D1 cells: abrogation of inhibition with oxytertacycline. Infect. Immun. 56: 3209–3215.PubMedGoogle Scholar
  74. Woolridge, K.G., Williams, P.H., and Ketley, J.M., 1996, Host signal transduction and endocytosis of Campylobacter jejuni, Microb. Pathog. 21: 299–305.CrossRefGoogle Scholar
  75. Xu, S., Cooper, A., Sturgill-Koszycki, S., van Heyningen, T., Chatterjee, D., Orme, I., Allen, P., and Russell, D.G., 1994, Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium infected macrophages, J. Immunol. 153: 2568–2578.PubMedGoogle Scholar
  76. Zhang, Y., and Rikihisa, Y., 1997, Tyrosine phosphorylation is required for ehrlichial internalization and replication in P388D1 cells, Infect. Immun. 65: 2959–2964.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Tobias A. Oelschlaeger
    • 1
  • Dennis J. Kopecko
    • 2
  1. 1.Institut für Molekulare InfektionsbiologieUniversität WuerzburgWuerzburgGermany
  2. 2.Laboratory of Enteric and Sexually Transmitted DiseasesFood and Drug AdministrationBethesdaUSA

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