Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Chlamydia pneumoniae — an infectious risk factor for atherosclerosis?

Key Points

  • Chlamydiae are obligate intracellular bacteria that have a unique developmental cycle in mammalian host cells.

  • Chlamydia pneumoniae is a human respiratory pathogen, which is in contrast to another human chlamydial pathogen, Chlamydia trachomatis, which causes ocular and genital infections.

  • Atherosclerosis is a chronic inflammatory disease that is characterized by the accumulation of modified low-density lipoproteins in the arterial wall.

  • C. pneumoniae infection has been recognized as a risk factor for atherosclerosis.

  • C. pneumoniae infection is ubiquitous. There is strong evidence indicating an association of antibodies against C. pneumoniae with an increased risk of coronary heart disease and other atherosclerotic diseases, such as strokes and aortic aneurysms.

  • C. pneumoniae has a tropism for atherosclerotic lesions and has been detected at high levels in atherosclerotic lesions.

  • C. pneumoniae infects endothelial cells, smooth-muscle cells and monocytes/macrophages, and induces inflammatory reactions that are commonly observed in atherosclerosis.

  • C. pneumoniae establishes a chronic infection in atherosclerotic lesions in hyperlipidaemic animals and promotes atherosclerosis C. pneumoniae and hyperlipidaemia are co-risk factors for atherosclerosis.

  • Antibiotic treatment for the prevention of acute cardiac events in humans has produced mixed results. Whether longer duration of treatment will be more effective is being evaluated.

Abstract

Cardiovascular disease, of which atherosclerosis is an important component, is the leading cause of death in the western world. Although there are well-defined risk factors for atherosclerosis, these factors do not account for all incidences of the disease. Because atherosclerotic processes are typified by chronic inflammatory responses, which are similar to those that are elicited by chronic infection, the role of infection in promoting or accelerating atherosclerosis has received renewed attention. This review focuses on the accumulating evidence that chronic infection with Chlamydia pneumoniae, a ubiquitous human respiratory pathogen, might contribute to atherosclerotic lesion progression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Developmental lifecycle of Chlamydia pneumoniae.
Figure 2: An electron micrograph showing a foam-cell macrophage containing Chlamydia pneumoniae.
Figure 3: Immunocytochemical staining of a fibrous plaque of the coronary artery.
Figure 4: Possible mechanisms by which Chlamydia pneumoniae might promote atherosclerosis.

Similar content being viewed by others

References

  1. Moulder, J. W., Hatch, T. P., Kuo, C. -C, Schachter, J. & Storz, J. in Bergey's Manual of Systematic Bacteriology Vol. 1 (ed. Krieg, N. R.) 729–739 (Williams and Wilkins, Baltimore, USA, 1984).

    Google Scholar 

  2. Grayston, J. T., Kuo, C. -C., Campbell, L. A. & Wang S. -P. Chlamydia pneumoniae sp. Nov. for Chlamydia strain TWAR. Int. J. Syst. Bacteriol. 39, 88–90 (1988). Classified TWAR as a new species of Chlamydia pneumoniae.

    Google Scholar 

  3. Grayston, J. T. et al. Evidence that Chlamydia pneumoniae causes pneumonia and bronchitis. J. Infect. Dis. 168, 1231–1235 (1993).

    CAS  PubMed  Google Scholar 

  4. Grayston, J. T. Background and current knowledge of Chlamydia pneumoniae and atherosclerosis. J. Infect. Dis. 181, S402–S410 (2000).

    CAS  PubMed  Google Scholar 

  5. Fuksuhi, H. & Hirai, K. Proposal of Chlamydia pecorum sp. nov. for Chlamydia strains derived from ruminants. Int. J. Syst. Bacteriol. 42, 306–308 (1992).

    Google Scholar 

  6. Wyrick, P. B. et al. Entry of genital Chlamydia trachomatis into polarized human epithelial cells. Infect. Immun. 57, 2378–2389 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Moulder, J. W. Interaction of chlamydiae and host cells in vitro. Microbiol. Rev. 55, 143–190 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuo, C. -C. & Grayston, J. T. Interaction of Chlamydia trachomatis organisms and HeLa 229 cells. Infect. Immun. 13, 1103–1109 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Raulston, J. E., Davis, C. H, Schmiel, D. H., Morgan, M. W. & Wyrick P. B. Molecular characterization and outer membrane association of a Chlamydia trachomatis protein related to the hsp70 family of proteins. J. Biol. Chem. 268, 23139–23147 (1993).

    CAS  PubMed  Google Scholar 

  10. Su, H., Watkins, N. G., Zhang, Y. X. & Caldwell, H. D. Chlamydia trachomatis–host cell interactions: role of the chlamydial major outer membrane protein as an adhesin. Infect. Immun. 58, 1017–1025 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, J. P. & Stephens, R. S. Mechanism of C. trachomatis attachment to eukaryotic host cells. Cell 69, 861–889 (1992).

    CAS  PubMed  Google Scholar 

  12. Chen, C. & Stephens, R. S. Chlamydia trachomatis glycosaminoglycan-dependent and independent attachment to eukaryotic cells. Microb. Pathogen. 22, 23–30 (1997).

    CAS  Google Scholar 

  13. Kuo, C. -C., Takahashi, N., Swanson, A. F., Ozeki, Y. & Hakomori, S. -I. An N-linked high-mannose type oligosaccharide, expressed at the major outer membrane protein of Chlamydia trachomatis, mediates attachment and infectivity of the microorganism to HeLa cells. J. Clin Invest. 98, 2813–2818 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuo, C. -C., Puolakkainen, M., Lin, T. -M., Witte, M. & Campbell, L. A. Mannose-receptor positive and negative mouse macrophages differ in their susceptibility to infection by Chlamydia species. Microb. Pathogen. 32, 43–48 (2002).

    CAS  Google Scholar 

  15. Wuppermann, F. N., Hegemann, J. H. & Jantos, C. A. Heparan sulfate-like glycosaminoglycan is a cellular receptor for Chlamydia pneumoniae. J. Infect. Dis. 184, 181–187 (2001).

    CAS  PubMed  Google Scholar 

  16. Nicholson, T. L, Olinger, L., Chong, K., Schoolnik G. & Stephens, R. S. Global stage-specific gene regulation during the developmental cycle of Chlamydia trachomatis. J. Bacteriol. 185, 3179–3189 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Xi, M., Bumgarner, R. E., Lampe, M. F. & Stamm, R. E. Chlamydia trachomatis infection alters host cell transcription in diverse cellular pathways. J. Infect. Dis. 187, 424–434 (2003).

    Google Scholar 

  18. Dwyer, R., Treharne, J. D., Jones, B. R. & Herring, J. Chlamydial infection. Results of micro-immunoflourescence tests for the detection of type specific antibody in certain chlamydial infections. Br. J. Vener. Dis. 56, 404–407 (1972).

    Google Scholar 

  19. Kuo, C. -C., Jackson, L. A., Campbell, L. A. & Grayston, J. T. Chlamydia pneumoniae (TWAR). Clin. Microbiol. Rev. 8, 451–461 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, S. -P. & Grayston, J. T. in Chlamydial Infections (eds Oriel, D., Ridgway, G., Schacter, J., Taylor-Robinson, D & Ward, M.) 329–332 (Cambridge Univ. Press, UK, 1986).

    Google Scholar 

  21. Kuo, C. -C., Chen, H. -H., Wang, S. -P. & Grayston, J. T. Identification of a new group of Chlamydia psittaci strains called TWAR. J. Clin. Microbiol. 24, 1034–1037 (1986). Reported the characterization of novel Chlamydia isolates from patients with respiratory infection. This seminal paper formed the basis for the classification of a new species.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Murray, C. J. L. & Lopez, L. D. Mortality by cause for eight regions of the world: global burden of disease study. Lancet. 349, 1269–1276 (1997).

    CAS  PubMed  Google Scholar 

  23. Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1998). An outstanding review of atherosclerosis as a disease of chronic inflammation.

    Google Scholar 

  24. Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hogg, N. & Berlin, C. Structure and function of adhesion receptors in leukocyte trafficking. Immunol. Today 16, 327–334 (1995).

    CAS  PubMed  Google Scholar 

  26. Poston, R. N., Haskard, D. O., Coucher, J. R. & Gall, M. N. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. Am. J. Pathol. 140, 665–673 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Johnson-Tidey, R. R., McGregor, J. L., Taylor, P. R. & Poston, R. N. Increase in adhesion molecule P-selectin in endothelium overlaying atherosclerotic plaques: coexpression with intercellular adhesion molecule-1. Am. J. Pathol. 144, 952–961 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cybulsky, M. I. & Gimbrone, M. A. Jr. Endothelial expression of a monocuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1994).

    Google Scholar 

  29. Iiyama, K. et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ. Res. 85, 199–207 (1999).

    CAS  PubMed  Google Scholar 

  30. Muller, W. A. et al. PECAM-1 is required for transendothelial migration of leukocytes. J. Exp. Med. 178, 449–460 (1993).

    CAS  PubMed  Google Scholar 

  31. O'Connor, S., Taylor, C., Campbell, L. A., Espstein, S. & Libby, P. Potential infectious etiologies of atherosclerosis. A multifactorial perspective. Emerg. Infect. Dis. 7, 780–788 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ngeh, J., Anand, V. & Gupta, S. Chlamydia pneumoniae and atherosclerosis — what we know and what we don't. Clin. Microbiol. Infect. 8, 2–13 (2002).

    CAS  PubMed  Google Scholar 

  33. Fabricant, C. G., Fabricant, J., Litrenta, M. M. & Minick, C. R. Virus-induced atherosclerosis. J. Exp. Med. 148, 335–340 (1978). The first report that demonstrates experimentally that an infectious agent can contribute to atherogenesis.

    CAS  PubMed  Google Scholar 

  34. Fabricant, C. G., Fabricant, J., Minick, C. R. & Litrenta, M. M. Herpesvirus-induced atherosclerosis in chickens. Fed. Proc. 42, 2476–2479 (1983).

    CAS  PubMed  Google Scholar 

  35. Wang, S. P. & Grayston, J. T. in Chlamydial Infections (eds Stephen, R. S. et al.) 155–158. (University of California, Berkeley, California, 1998). Summarizes seroepidemiological studies on C. pneumoniae using the micro-immunflourescence test, showing the population prevalence of infection and that everyone is infected in their lifetime.

    Google Scholar 

  36. Saikku, P. et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2, 983–986 (1988). The first report linking C. pneumoniae to atherosclerosis.

    CAS  PubMed  Google Scholar 

  37. Kuo, C. -C. & Campbell, L. A. Chlamydial infection of the cardiovascular system. Front. Biosci. 8, e36–e42 (2003).

    PubMed  Google Scholar 

  38. Peeling, R. W. et al. Chlamydia pneumoniae serology: interlaboratory variation in microimmunofluorescence assay results. J. Infect. Dis. 181, S426–S429 (2000).

    CAS  PubMed  Google Scholar 

  39. Shor, A., Kuo, C. C. & Patton, D. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S. Afr. Med. J. 82, 158–161 (1992).

    CAS  PubMed  Google Scholar 

  40. Kuo, C. -C. et al. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J. Infect. Dis. 167, 841–849 (1993). The first comprehensive study demonstrating the presence of the organism in atherosclerotic lesions.

    CAS  PubMed  Google Scholar 

  41. Kuo, C. -C. & Campbell, L. A. Detection of Chlamydia pneumoniae in arterial tissues. J. Infect. Dis. 181, S432–S436 (2000).

    CAS  PubMed  Google Scholar 

  42. Taylor-Robinson, D. & Thomas, B. J. Chlamydia pneumoniae in atherosclerotic tissue. J. Infect. Dis. 181, S437–S443 (2000).

    CAS  PubMed  Google Scholar 

  43. Ramirez, J. et al. Isolation of Chlamydia pneumoniae (Cpn) from the coronary artery of a patient with coronary atherosclerosis. Ann. Int. Med. 125, 979–982 (1996). The first report on the isolation of C. pneumoniae from atherosclerotic tissue.

    CAS  PubMed  Google Scholar 

  44. Jackson, L., Campbell, L. A., Kuo, C. -C., Lee, A. & Grayston, J. T. Isolation of Chlamydia pneumoniae from a carotid endarctarterectomy specimen. J. Infect. Dis. 176, 292–295 (1997).

    CAS  PubMed  Google Scholar 

  45. Maass, M. et al. Endovascular presence of viable Chlamydia pneumoniae is a common phenomenon in coronary artery disease. J. Am. Coll. Cardiol. 31, 827–832 (1998).

    CAS  PubMed  Google Scholar 

  46. Kuo, C. -C., Gown, A. M., Benditt, E. P. & Grayston, J. T. Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain. Arterioscler. Thromb. 13, 1501–1504 (1993). This report identified C. pneumoniae in foam cells derived from macrophages and smooth-muscle cells in the atherosclerotic lesion.

    CAS  PubMed  Google Scholar 

  47. Ouchi, K. et al. Chlamydia pneumoniae in atherosclerotic and nonatherosclerotic tissue. J. Infect. Dis. 181, S441–S443 (2000).

    CAS  PubMed  Google Scholar 

  48. Puolakkainen, M., Kuo, C. -C., Wang, S. -P., Grayston, J. T. & Campbell, L. A. Serological response to Chlamydia pneumoniae in adults with coronary arterial fatty streaks and fibrolipid plaques. J. Clin. Microbiol. 31, 2212–2214 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Maass, M., Geiffers, J., Krause, E. & Engel, P. M. Poor correlation between microimmunofluorescence serology and polymerase chain reaction for detection of vascular Chlamydia pneumoniae infection in CAD patients. Med. Microbiol. Immunol. 187, 103–106 (1998).

    CAS  PubMed  Google Scholar 

  50. Boman, J. et al. High prevalence of Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in patients with cardiovascular disease and in middle-aged blood donors. J. Infect. Dis. 178, 274–277 (1998). The first demonstration of the presence of the organism in circulating monocytes in humans.

    CAS  PubMed  Google Scholar 

  51. Smieja, M., Mahony, J., Petrich, A., Boman, J. & Chernesky, M. Association of circulating Chlamydia pneumoniae DNA with cardiovascular disease: a systematic review. BMC Infect. Dis. 2, 21 (2002).

    PubMed  PubMed Central  Google Scholar 

  52. Grayston, J. T., Wang, S. -P., Yeh, L. -L. & Kuo, C. -C. Importance of reinfection in the pathogenesis of trachoma. Rev. Infect. Dis. 7, 717–725 (1985).

    CAS  PubMed  Google Scholar 

  53. Godzik, K., O'Brien, E. R., Wang, S. -P. & Kuo, C. C. In vitro susceptibility of human vascular wall cells to infection with Chlamydia pneumoniae. J. Clin. Microbiol. 33, 2411–2414 (1995). Shows that endothelial cells, macrophages, and smooth-muscle cells are susceptible to infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gaydos, C. A., Summersgill, J. T., Sahney, N. N., Ramierez, J. A. & Quinn, T. C. Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect. Immun. 64, 1614–1620 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lin, T. -M., Campbell, L. A., Rosenfeld, M. E. & Kuo, C. -C. Monocyte-endothelial cell coculture enhances infection of endothelial cells with Chlamydia pneumoniae. J. Infect Dis. 181, 1096–1100 (2000).

    CAS  PubMed  Google Scholar 

  56. Puolakkainen, M. et al. Cell-to-cell contact of human monocytes with infected arterial smooth-muscle cells enhances growth of Chlamydia pneumoniae. J. Infect. Dis. 187, 435–440 (2003).

    CAS  PubMed  Google Scholar 

  57. Kalayoglu, M. V., Perkins, B. N. & Bryne, G. I. Chlamydia pneumoniae-infected monocytes exhibited increased adherence to human aortic endothelial cells. Microbe. Infect. 3, 963–969 (2001).

    CAS  Google Scholar 

  58. Kaukoranta-Rolvanen, S. S., Ronni, T., Leinonen, M., Saikku, P. & Laitinen, K. Expression of adhesion molecules on endothelial cells stimulated by Chlamydia pneumoniae. Microb. Pathog. 21, 407–411 (1996). Describes one mechanism by which Chlamydia pneumoniae could contribute to atherosclerotic processes.

    Google Scholar 

  59. Coombes, B. K. & Mahony, J. B. cDNA array analysis of altered gene expression in human endothelial cells in response to Chlamydia pneumoniae infection. Infect. Immun. 69, 1420–1427 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Coombes, B. K., Chiu, B., Fong, I. W. & Mahony, J. B. Chlamydia pneumoniae infection of endothelial cells induces transcriptional activation of platelet-dervied growth factor: a potential link to intimal thickening in a rabbit model of atherosclerosis. J. Infect. Dis. 185, 1621–1630 (2002).

    CAS  PubMed  Google Scholar 

  61. Heinemann, M., Susa, M., Simnacher, U., Marre, R. & Essig, A. Growth of Chlamydia pneumoniae induces cytokine production and expression of CD14 in a human monocytic cell line. Infect. Immun. 64, 4872–4875 (1996). Describes another mechanism by which Chlamydia pneumoniae could contribute to inflammatory processes of atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Summmersgill, J. T., Molestina, R. E., Miller, R. D. & Ramirez, J. A. Interactions of Chlamydia pneumoniae with human endothelial cells. J. Infect. Dis. 181, S479–S482 (2000).

    Google Scholar 

  63. Kol, A., Bourcier, T., Lichtman, A. H. & Libby, P. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J. Clin. Invest. 103, 571–577 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Dechend, R. et al. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae induced cell interaction and activation. Circulation 108, 261–265 (2003).

    CAS  PubMed  Google Scholar 

  65. Kothe, H. et al. Hydroxymethylglutaryl coenzyme A reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with Chlamydia pneumoniae. Circulation 101, 1760–1763 (2000).

    CAS  PubMed  Google Scholar 

  66. Kalayoglu, M. V. & Byrne, G. I. Induction of macrophage foam-cell formation by Chlamydia pneumoniae. J. Infect. Dis. 177, 725–729 (1998). This elegant paper demonstrated that C. pneumoniae could induce foam-cell formation in macrophages, which provide a mechanism by which C. pneumoniae could exacerbate atherosclerosis.

    CAS  PubMed  Google Scholar 

  67. Kalayoglu, M. V. et al. Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions. J. Infect. Dis., 181, S483–S489 (2000).

    CAS  PubMed  Google Scholar 

  68. Blessing, E. et al. Foam cell inhibits growth of Chlamydia pneumoniae but does not attenuate Chlamydia pneumoniae induced secretion of pro-inflammatory cytokines. Circulation 105, 1976–1982 (2002).

    CAS  PubMed  Google Scholar 

  69. Choi, E. Y. et al. Upregulation of extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases in human atherosclerosis infected with Chlamydia pneumoniae: The potential role of Chlamydia pneumoniae infection in the progression of atherosclerosis. Exp. Mol. Med. 31, 391–400 (2002).

    Google Scholar 

  70. Kol, A., Sukhova, G. K., Lichtman, A. H. & Libby, P. Chlamydial heat shock protein 60 localized in human atheroma and regulates macrophage tumor necrosis factor-α and matrix metalloproteinase expression. Circulation 98, 300–307 (1998). Showed the presence of a C. pneumoniae antigen associated with a delayed type-hypersensitivity response in the atherosclerotic lesion and that C. pneumoniae could induce an enzyme that leads to plaque destabilization.

    CAS  PubMed  Google Scholar 

  71. Bea, F. et al. Chlamydia pneumoniae induces tissue factor expression in mouse macrophages via activation of Egr-1 and the MEK-ERK1/2 pathway. Circ. Res. 92, 394–401 (2003). Showed that induction of tissue factor, a pro-thrombotic molecule, was by activation of the transcription factor EGR-1, which is pro-atherogenic.

    CAS  PubMed  Google Scholar 

  72. Fryer, R. H., Schwobe, E. P., Woods, M. L. & Rogers, G. M. Chlamydia species infect human vascular endothelial cells and induce procoagulant activity. J. Investig. Med. 45, 168–174 (1997).

    CAS  PubMed  Google Scholar 

  73. Dechend, R. et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-κB and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis. Circulation 100, 1369–1373 (1999).

    CAS  PubMed  Google Scholar 

  74. McCaffrey, T. A. et al. High-level expression of Egr-1 and Egr-1-inducible genes in mouse and human athersoclerosis. J. Clin. Invest. 105, 653–662 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Silverman, E. S. & Collins, T. Pathways of Egr-1-mediated gene transcription in vascular biology. Am. J. Pathol. 154, 665–670 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Reddick, R. L., Zhang, S. H. & Maeda, N. Atherosclerosis in mice lacking apoE. Arterioscler. Thromb. 4, 141–147 (1994).

    Google Scholar 

  77. Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L. & Ross, R. ApoE deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).

    CAS  PubMed  Google Scholar 

  78. Moazed, T. C., Kuo, C. -C., Grayston, J. T. & Campbell, L. A. Evidence of systemic dissemination of C. pneumoniae infection via macrophages in the mouse. J. Infect. Dis. 177, 132–135 (1998). This paper shows how C. pneumoniae disseminates from the lungs to other anatomic sites.

    Google Scholar 

  79. Moazed, T. C., Kuo, C. -C., Grayston, J. T. & Campbell, L. A. Murine models of C. pneumoniae infection and atherosclerosis. J. Infect. Dis. 175, 883–890 (1997).

    CAS  PubMed  Google Scholar 

  80. Jackson, L. A. et al. Specificity of detection of Chlamydia pneumoniae in cardiovascular and non-cardiovascular tissues: evaluation of the innocent bystander hypothesis. Am. J. Pathol. 150, 1785–1790 (1997). This report demonstated the tissue tropism of C. pneumoniae for the atherosclerotic lesions.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Grnhagen-Riska, C., Saikku, P., Riska, H., Froseth, B. & Grayston, J. T. in Sarcoidosis and Other Granulomatous Disorders (eds Grassi, C., Rizzato, G. & Pozzi, E.) 297–301 (Excerpta Medicine, Amsterdam, Holland, 1988).

    Google Scholar 

  82. Puolakkainen, M. et al. Serological response to Chlamydia pneumoniae in patients with sarcoidosis. J. Infect. 33, 199–205 (1996).

    CAS  PubMed  Google Scholar 

  83. Moazed, T. C., Campbell, L. A., Rosenfeld, M. E., Grayston, J. T. & Kuo, C. -C. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. J. Infect. Dis. 180, 238–241 (1999).

    CAS  PubMed  Google Scholar 

  84. Rothstein, N. M., Quinn, T. C., Madico, G., Gaydos, C. A. & Lowenstein, C. J. Effect of azithromycin on murine arteriosclerosis exacerbated by Chlamdyia pneumoniae. J. Infect. Dis. 183, 232–238 (2001).

    CAS  PubMed  Google Scholar 

  85. Burnett, M. S et al. Atherosclerosis in apoE knockout mice infected with multiple pathogens. J. Infect. Dis. 183, 226–231 (2001).

    CAS  PubMed  Google Scholar 

  86. Hu, H., Pierce, G. N. & Zhong, G. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J. Clin. Invest. 103, 747–753 (1999). References 83 and 86 demonstrate that C. pneumoniae accelerates atherosclerosis in hyperlipidaemic mouse models.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Blessing, E., Campbell, L. A., Rosenfeld, M. E. & Kuo, C. -C. Chlamydia pneumoniae infection accelerates hyperlipidemia induced atherosclerotic lesion development in C57BL/6J mice. Atherosclerosis. 158, 13–17 (2001).

    CAS  PubMed  Google Scholar 

  88. Muhlestein, J. B. et al. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. 97, 633–636 (1998). This report shows that C. pneumoniae infection accelerated atherosclerosis in a rabbit model and that the acceleration could be prevented by treatment with an anti-chlamydial antibiotic.

    CAS  PubMed  Google Scholar 

  89. Fong, I. W., Chiu, B., Viira, E., Jang, D. & Mahoney, J. B. Influence of clarithromycin on early atherosclerotic lesions after Chlamydia pneumoniae infection in a rabbit model. Antimicrob. Agents Chemother. 46, 2321–2326 (2002). This report shows that early administration of antibiotics post-infection is crucial in preventing acceleration of atherosclerosis by C. pneumoniae.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Caligiuri, G., Rottenberg, M., Nicoletti, A., Wigzell, H. & Hansson, G. K. Chlamydia pneumoniae infection does not induce or modify atherosclerosis in mice. Circulation 103, 2834–2838 (2001).

    CAS  PubMed  Google Scholar 

  91. Aalto-Setala, K. et al. Chlamdyia pneumoniae does not increase atherosclerosis in the aortic root of apolipprotein E-deficient mice. Arteroscler. Thromb. Vasc. Biol. 21, 578–584 (2001).

    CAS  Google Scholar 

  92. Blessing, E. et al. Chlamdyia pneumoniae induces inflammatory changes in the heart and aorta of normolipidemic C57BL/6J mice. Infect. Immun. 68, 4765–4768 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Laitinen, K., Laurila, A., Pyhala, L., Leinonen, M. & Saikku, P. Chlamydia pneumoniae infection induces inflammatory changes in the aorta of rabbits. Infect. Immun. 65, 4832–4835 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Fong, I. W. et al. De novo induction of atherosclerosis by Chlamydia pneumoniae in a rabbit model. Infect. Immun. 67, 648–655 (1999)

    Google Scholar 

  95. Blessing, E., Campbell, L. A., Rosenfeld, M. E. & Kuo, C. -C. Chlamydia pneumoniae and hyperlipidemia are co-risk factors for atherosclerosis: infection prior to induction of hyperlipidemia does not accelerate development of atherosclerotic lesions in C57BL/6J mice. Infect. Immun. 70, 5332–5334 (2002). Demonstrated that C. pneumoniae and hyperlipidaemia are co-risk factors for atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Pislaru, S. V. et al. Chlamydia pneumoniae induces neointima formation in coronary arteries of normal pigs. Cardiovas. Res. 57, 834–843 (2003).

    CAS  Google Scholar 

  97. Liuba, P. et al. Endothelial dysfunction after repeated Chlamydia pneumoniae infection in apolipoprotein E-knockout mice. Circulation 102, 1039–1044 (2000). Showed that C. pneumoniae impairs relaxation of the artery.

    CAS  PubMed  Google Scholar 

  98. Liuba, P. et al. Acute Chlamydia pneumoniae infection causes coronary endothelial dysfunction in pigs. Atherosclerosis 167, 215–222 (2003).

    CAS  PubMed  Google Scholar 

  99. Kuvin, J. T. et al. Effect of short-term antibiotic treatment on Chlamydia pneumoniae and peripheral endothelial function. Am. J. Cardiol. 91, 732–735 (2003).

    CAS  PubMed  Google Scholar 

  100. Ezzahiri, R. et al. Chlamydia pneumoniae infection induces and unstable atherosclerotic plaque phenotype in LDL-receptor, ApoE double knockout mice. Eur. J. Vasc. Endovasc. Surg. 26, 88–95 (2003)

    CAS  PubMed  Google Scholar 

  101. Malinverni, R., Kuo, C. -C., Campbell, L. A., Lee, A. & Grayston J. T. Experimental Chlamydia pneumoniae (TWAR) pneumonitis: effect of two antibiotic regimens on the course and persistence of infection. Antimicrob. Agents. Chemother. 39, 45–49 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Fong, I. W. Antibiotics effects in a rabbit model of Chlamydia pneumoniae-induced atherosclerosis. J. Infect. Dis. 181, S514–S518 (2000).

    CAS  PubMed  Google Scholar 

  103. Grayston, J. T. Antibiotic treatment of atherosclerotic cardiovascular disease. Circulation 107, 1228–1230 (2003). A good review summarizing antibiotic treatment trials.

    PubMed  Google Scholar 

  104. O'Connor, C. M. et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 290, 1459–1466 (2003).

    CAS  PubMed  Google Scholar 

  105. Beatty. W., Morrison, R. P. & Byrne, G. I. Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microb. Rev. 58, 686–699 (1994). An excellent review on the microbiology of chlamydiae, emphasizing the establishment of persistent infection.

    CAS  Google Scholar 

  106. Gieffers, J. et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 103, S1–S6 (2001).

    Google Scholar 

  107. Campbell, L. A., Marrazzo, J. M., Stamm, W. E. & Kuo, C. -C in Laboratory Diagnosis of Bacterial Infections (ed. Cimolai, N.) 795–821 (Marcel Dekker, New York, 2001).

    Google Scholar 

  108. Kuo, C. -C. et al. Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15–34 years old). Proc. Natl Acad. Sci. USA 92, 6911–6914 (1995).

    CAS  PubMed  Google Scholar 

  109. Kalayoglu, M. V., Libby, P. & Byrne, G. I. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 288, 2724–2731 (2002).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lee Ann Campbell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

TW183

LocusLink

TNF-α

IL-8

SwissProt

apolipoprotein E

E-selectin

ICAM-1

LDL-receptor

PECAM-1

P-selectin

VCAM-1

Glossary

OBLIGATE

The ability to survive only in a particular environment. The chlamydiae are obligate intracellular bacteria because chlamydiae survive only inside the host cell, like viruses.

NON-PROFESSIONAL PHAGOCYTIC CELLS

Cells other than mononuclear and polymorphonuclear leukocytes (professional phagocytes), which have the ability to take up pathogenic microorganisms.

MICRO-IMMUNOFLUORESCENCE TEST

An indirect fluorescent antibody test for measuring serum and tear antibodies to chlamydial organisms and for the serological typing of chlamydial isolates. Formalin-fixed whole chlamydial elementary bodies or organisms are used as antigens.

INTIMA

(Tunica intima vasorum). The inner-lining of blood vessels — the layer underneath the endothelium and above the media (smooth-muscle layer).

THROMBUS

An aggregation of platelets and fibrin, which can cause vascular obstruction.

PROSPECTIVE STUDY

A clinical study in which the analysis of the outcome was based on the data that were collected after the completion of a pre-designed study.

ATHEROMAS

An atherosclerotic plaque.

CHRONIC INFECTION

An infection that persists over a long period of time.

MITOGEN

A substance that induces cell proliferation.

SARCOIDOSIS

A granulomatous disease of unknown aetiology that can involve almost any organ or tissue.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campbell, L., Kuo, Cc. Chlamydia pneumoniae — an infectious risk factor for atherosclerosis?. Nat Rev Microbiol 2, 23–32 (2004). https://doi.org/10.1038/nrmicro796

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro796

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing