Type III Secretion, Contact-dependent Model for the Intracellular Development of Chlamydia

  • D. P. Wilson
  • P. Timms
  • D. L. S. Mcelwain
  • P. M. Bavoil
Original Paper


The medically significant genus Chlamydia is a class of obligate intracellular bacterial pathogens that replicate within vacuoles in host eukaryotic cells termed inclusions. Chlamydia's developmental cycle involves two forms; an infectious extracellular form, known as an elementary body (EB), and a non-infectious form, known as the reticulate body (RB), that replicates inside the vacuoles of the host cells. The RB surface is covered in projections that are in intimate contact with the inclusion membrane. Late in the developmental cycle, these reticulate bodies differentiate into the elementary body form. In this paper, we present a hypothesis for the modulation of these developmental events involving the contact-dependent type III secretion (TTS) system. TTS surface projections mediate intimate contact between the RB and the inclusion membrane. Below a certain number of projections, detachment of the RB provides a signal for late differentiation of RB into EB. We use data and develop a mathematical model investigating this hypothesis. If the hypothesis proves to be accurate, then we have shown that increasing the number of inclusions per host cell will increase the number of infectious progeny EB until some optimal number of inclusions. For more inclusions than this optimum, the infectious yield is reduced because of spatial restrictions. We also predict that a reduction in the number of projections on the surface of the RB (and as early as possible during development) will significantly reduce the burst size of infectious EB particles. Many of the results predicted by the model can be tested experimentally and may lead to the identification of potential targets for drug design.


Chlamydia Type III secretion Contact dependence Intracellular development Mathematical model 


  1. Aldous, M.B., Grayston, J.T., Wang, S.P., Foy, H.M., 1992. Seroepidemiology of Chlamydia pneumoniae TWAR infection in Seattle families, 1966–1979. Infect. Dis. 166, 646.Google Scholar
  2. Bavoil, P., Hsia, R.C., Ojcius, D.M., 2000. Closing in on Chlamydia and its intracellular bag of tricks. Microbiology 146, 2723.Google Scholar
  3. Bavoil, P.M., Hsia, R.C., 1998. Type III secretion in Chlamydia. A case of déjà vu? Mol. Microbiol. 28, 860.Google Scholar
  4. Campbell, L.A., Kuo, C.C., 2003. Chlamydia pneumoniae and atherosclerosis. Semin. Respir. Infect. 18, 48.CrossRefGoogle Scholar
  5. Fields, K.A., Hackstadt, T., 2000. Evidence for the secretion of Chlamydia trachomatis CopN by a type III secretion mechanism, Mol. Microbiol. 38, 1048.Google Scholar
  6. Fields, K.A., Mead, D.J., Dooley, C.A., Hackstadt, T., 2003. Chlamydia trachomatis type III secretion: evidence for a functional apparatus during early-cycle development, Mol. Microbiol. 48, 671.Google Scholar
  7. Forsberg, A., Viitanen, A.M., Skurnik, M., Wolf-Watz, H., 1991. The surface-located YopN protein is involved in calcium signal transduction in Yersinia pseudotuberculosis. Mol. Microbiol. 5, 977.CrossRefGoogle Scholar
  8. Hackstadt, T., Fischer, E.R., Scidmore, M.A., Rockey, D.D., Heinzen, R.A., 1997. Origins and functions of the chlamydial inclusion. Trends Microbiol. 5, 288.CrossRefGoogle Scholar
  9. Hackstadt, T., Scidmore-Carlson, M., Shaw, E., Fischer, E., 1999. The Chlamydia trachomatis IncA protein is required for homotypic vesicle fusion. Cell Microbiol. 1, 119.CrossRefGoogle Scholar
  10. Hensel, M., Shea, J.E., Waterman, S.R., Mundy, R., Nikolaus, T., Banks, G., Vazquez-Torres, A., Gleeson, C., Fang, F.C., Holden, D.W., 1998. Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages. Mol. Microbiol. 30, 163.CrossRefGoogle Scholar
  11. Horn, M., Collingro, A., Schmitz-Esser, S., Beier, C.L., Purkhold, U., Fartmann, B., Brandt, P., Nyakatura, G.J., Droege, M., Frishman, D., Rattei, T., Mewes, H.W., Wagner, M., 2004. Illuminating the evolutionary history of chlamydiae. Science 304, 728.CrossRefGoogle Scholar
  12. Hsia, R.C., Pannekoek, Y., Ingerowski, E., Bavoil, P.M., 1997. Type III secretion genes identify a putative virulence locus of Chlamydia, Mol. Microbiol. 25, 351.Google Scholar
  13. Hueck, C.J., 1998. Type III protein secretion systems in bacterial pathogens of animals and plants, Microbiol. Mol. Biol. Rev. 62, 379.Google Scholar
  14. Johnson, F.W.A., Chancerelle, L.Y.J., Hobson, D., 1978. An improved method for demonstrating the growth of chlamydiae in tissue culture. Med. Lab. Sci. 35, 67.Google Scholar
  15. Kalman, S., Mitchell, W., Marathe, R., Lammel, C., Fan, J., Hyman, R.W., Olinger, L., Grimwood, J., Davis, R.W., Stephens, R.S., 1999. Comparative genomes of Chlamydia pneumoniae and C. trachomatis. Nat. Genet. 21, 385.CrossRefGoogle Scholar
  16. Mathews, S.A., Volp, K.M., Timms, P., 1999. Development of a quantitative gene expression assay for Chlamydia trachomatis identified temporal expression of σ factors. FEBS Lett. 458, 354.CrossRefGoogle Scholar
  17. Matsumoto, A., 1973. Fine structures of cell envelopes of Chlamydia organisms as revealed by freeze-etching and negative staining techniques. J. Bacteriol. 116, 1355.Google Scholar
  18. Matsumoto, A., 1981a. Electron Microscopic Observations of surface projections and related intracellular structures of Chlamydia organisms. J. Electron. Microsc. 30, 315.Google Scholar
  19. Matsumoto, A., 1981b. Isolation and electron microscopic observations of intracytoplasmic inclusions containing Chlamydia psittaci. J. Bacteriol. 145, 605.Google Scholar
  20. Matsumoto, A., 1982. Electron microscopic observations of surface projections on Chlamydia psittaci reticulate bodies. J. Bacteriol. 150, 358.Google Scholar
  21. Matsumoto, A., Bessho, I., Uchira, K., Suda, T., 1991. Morphological studies of the association of mitochondria with chlamydial inclusions and the fusion of chlamydial inclusions, J. Electron. Micro. 40, 356.Google Scholar
  22. Matsumoto, A., Fujiwara, E., Higashi, N., 1976. Observations of the surface projections of infectious small cell of Chlamydia psittaci in thin sections. J. Electron. Microsc. 25, 169.Google Scholar
  23. Matsumoto, A., Higashi, N., Tamura, A., 1973. Electron microscope observations on the effects of polymixin B sulfate on cell walls of Chlamydia psittaci. J. Bacteriol. 113, 357.Google Scholar
  24. Moulder, J.W., 1991. Interaction of chlamydiae and host cells in vitro. Microbiol. Rev. 55, 143.Google Scholar
  25. Read, T.D., Brunham, R.C., Shen, C., Gill, S.R., Heidelberg, J.F., White, O., Hickey, E.K., Peterson, J., Utterback, T., Berry, K., Bass, S., Linher, K., Weidman, J., Khouri, H., Craven, B., Bowman, C., Dodson, R., Gwinn, M., Nelson, W., DeBoy, R., Kolonay, J., McClarty, G., Salzberg, S.L., Eisen, J., Fraser, C.M., 2000. Genome sequences of Chlamydia trachomatis MoPn and Chlamydia pneumoniae AR39. Nucleic Acids Res. 28, 1397.CrossRefGoogle Scholar
  26. Read, T.D., Myers, G.S., Brunham, R.C., Nelson, W.C., Paulsen, I.T., Heidelberg, J., Holtzapple, E., Khouri, H., Federova, N.B., Carty, H.A., Umayam, L.A., Haft, D.H., Peterson, J., Beanan, M.J., White, O., Salzberg, S.L., Hsia, R.C., McClarty, G., Rank, R.G., Bavoil, P.M., Fraser, C.M., 2003. Genome sequence of Chlamydophila caviae (Chlamydia psittaci GPIC): Examining the role of niche-specific genes in the evolution of the Chlamydiaceae. Nucleic Acids Res. 31, 2134.CrossRefGoogle Scholar
  27. Rockey, D.D., Matsumoto, A., 1999. The chlamydial developmental cycle. In: Brun, Y.V., Shimkets, L.J. (Eds.), Prokaryotic Development. ASM Press, Washington, DC, pp. 403–425.Google Scholar
  28. Shaw, E.I., Dooley, C.A., Fischer, E.R., Scidmore, M.A., Fields, K.A., Hackstadt, T., 2000. Three temporal classes of gene expression during the Chlamydia trachomatis developmental cycle. Mol. Microbiol. 37, 913.CrossRefGoogle Scholar
  29. Shirai, M., Hirakawa, H., Kimoto, M., Tabuchi, M., Kishi, F., Ouchi, K., Shiba, T., Ishii, K., Hattori, M., Kuhara, S., Nakazawa, T., 2000. Comparison of whole genome sequences of Chlamydia pneumoniae J138 from Japan and CWL029 from USA. Nucleic Acids Res. 28, 2311.CrossRefGoogle Scholar
  30. Spears, P., Storz, J., 1979. Biotyping of Chlamydia psittaci based on inclusion morphology and response to diethylaminoethyl-dextran and cycloheximide. Infect. Immun. 24, 224.Google Scholar
  31. Stephens, R.S., Kalman, S., Lammel, C., Fan, J., Marathe, R., Aravind, L., Mitchell, W., Olinger, L., Tatusov, R.L., Zhao, Q., Koonin, E.V., Davis, R.W., 1998. Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis. Science 282, 638.CrossRefGoogle Scholar
  32. Suchland, R.J., Rockey, D.D., Bannantine, J.P., Stamm, W.E., 2000. Isolates of Chlamydia trachomatis that occupy non-fusogenic inclusions lack IncA, a protein localized to the inclusion membrane. Infect. Immun. 68, 360.Google Scholar
  33. Tamura, A., Matsumoto, A., Manire, G.P., Higashi, N., 1971. Electron microscopic observations on the structure of the envelopes of mature elementary bodies and developmental reticulate forms of Chlamydia psittaci. J. Bacteriol. 105, 355.Google Scholar
  34. Thylefors, B., Negral, A. D., Parajasegaram, R., Dadzie, K. Y., 1995. Global data on blindness. Bull. World Health Org. 73, 115.Google Scholar
  35. Ward, M., 1995. The immunobiology and immunopathology of chlamydial infections. APMIS 103, 769.CrossRefGoogle Scholar
  36. Ward, M.E., 1983. Cqhlamydial classification, development and structure. Br. Med. Bull. 39, 109.Google Scholar
  37. Wilson, D.P., Mathews, S., Wan, C., Pettitt, A.N., McElwain, D.L.S., 2004. Use of a quantitative gene expression array based on micro-array techniques and a mathematical model for the investigation of chlamydial generation time. Bull. Math. Biol. 66, 523.CrossRefMathSciNetGoogle Scholar

Copyright information

© Society for Mathematical Biology 2006

Authors and Affiliations

  • D. P. Wilson
    • 1
    • 2
  • P. Timms
    • 3
  • D. L. S. Mcelwain
    • 1
  • P. M. Bavoil
    • 4
  1. 1.School of Mathematical SciencesQueensland University of TechnologyBrisbaneAustralia
  2. 2.Department of BiomathematicsUniversity of CaliforniaLos AngelesUSA
  3. 3.School of Life SciencesQueensland University of TechnologyBrisbaneAustralia
  4. 4.Department of Biomedical SciencesUniversity of Maryland Dental SchoolBaltimoreUSA

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