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Experimental studies

The case for a causal role of C. pneumoniae in coronary artery disease would be greatly strengthened if plausible molecular or cellular mechanisms involving known risk factors could be identified. This section reviews some of the experimental evidence obtained from studies at the cellular level or in whole animals.

Cellular studies

A key challenge is to understand at the cellular level how C. pneumoniae might cause atherogenesis [lay reader: the formation of fatty plaque in the coronary artery that leads to heart disease]. It is known that C. pneumoniae is able to infect most of the key cells involved in  atherogenesis, including macrophages, endothelium and smooth muscle cells. However, the ability of the organism to replicate in matured human macrophages is very limited [Airenne et al., 1998]. There is considerable evidence that atherogenesis is partly driven by inflammatory stimuli, notably the pro-inflammatory cytokines. Chlamydiae are capable of interacting with macrophages or epithelia to generate a variety of pro-inflammatory cytokines [see: chlamydiae and cytokines]. Two other key events in atherogenesis are: 1)  the transformation of macrophages into fat-laden foam cells as a result of the uptake of low density lipoproteins (LDL) via the classic Apo B/E receptor, resulting in the accumulation of cholesteryl esters and; 2)  the oxidation  of lipoproteins at the site of lesion development, resulting in tissue damage. Normally macrophages do not take up exogenous LDL to an excessive extent because the Apo B/E receptor is rapidly down regulated by the intracellular accumulation of cholesteryl esters derived from the internalised LDL. However, C. pneumoniae-infected human or mouse macrophages accumulate LDL resulting in their transformation into cholesterol-laden foam cells [Kalayoglu & Byrne 1998b]. This process does not required the prior oxidation of LDL before uptake, since it occurs in the presence of anti-oxidants, and it involves an unknown mechanism independent of the classic Apo B/E receptor since it occurs in LDL-receptor-deficient, knock out mice [Kalayoglu et al., 2000]. The precise mechanism of chlamydial-induced LDL uptake remains to be determined. It may involve chlamydial modification of LDL prior to uptake, participation of an unknown receptor and / or interference with the normal macrophage cholesterol ester pump out mechanisms, such as that, in Tangier disease, involving the ATP-binding cassette transporter 1 (ABC1) [Rust et al., 1999]. In this latter context it should be remembered that chlamydiae interfere with the normal intracellular trafficking of lipid and membranes within cells [see: membrane trafficking]. Chlamydial lipopolysaccharide is thought to be a major trigger of chlamydial-induced LDL uptake [Kalayoglu & Byrne, 1998a]. 

[Comment: It should be noted  that C. trachomatis is also capable of inducing LDL uptake and macrophage - foam cell transformation.  The question therefore arises why C. pneumoniae alone is the chlamydial species particularly associated with heart disease?]

With respect to lipid oxidation, chlamydial heat shock protein chsp60 induced monocyte LDL oxidation in a dose dependent manner, whereas another chlamydial heat shock protein, chsp10, did not [Kalayoglu et al., 1999a; 2000]. Chsp60 has been identified within human atheromatous tissue, is highly immunogenic and pro-inflammatory and is thought to be associated with the immunopathology of chlamydial disease [Kalayoglu et al., 2000;  see: chlamydial heat shock protein and disease]. Chsp60 also promotes matrix metalloproteinase and cytokine production by monocytes, and cytokine production by monocytes, endothelial cells and smooth muscle cells. Thus chsp60 may function both as a direct antigenic and inflammatory stimulant and as a transducer of unknown cellular signalling systems leading to cellular activation within the atheromatous plaque [Kalayoglu et al., 2000].  [MEW]

Animal studies

There is quite strong evidence from some studies in experimental animals that C. pneumoniae has a role in atherosclerosis. The initial studies indicated that C. pneumoniae infection exacerbates atherosclerosis [Moazed et al., 1999; Burnett et al., 2001], although the presence of hypercholesterolaemia may be required [Muhlestein et al., 1998; Hu, Pierce & Zhong, 1999], as is clearly shown in the following picture:

There is also evidence that antibiotics prevent the exacerbating effects of C. pneumoniae infection  on atherosclerosis [Fong et al., 1999; Muhlestein et al., 1998].

However, the evidence that C. pneumoniae causes atherosclerosis in other animal models is not convincing, since studies have either reported no effect [Wright et al., 2000; Caligiuri et al., 2001] or observed only inflammatory or [possible] early atherosclerotic changes  [Blessing et al., 2000; Fong et al., 1997; Fong et al., 1999; Laitinen et al., 1997].

 [YW] Jan 2002

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References

Airenne, S., Surcel, H. M., Alakarppa, H., Laitinene, K., Saikku, P. & Laurila, A. (1998). Characterization of Chlamydia pneumoniae infection in human monocytes, pp 123 - 126 In: Stephens, R. S. et al., eds., Chlamydial infections. Proceedings of the ninth international symposium on human chlamydial infections. International Chlamydia Symposium, San Francisco.

Blessing, E., Lin, T. M., Campbell, L. A., Rosenfeld, M. E., Lloyd, D. & Kuo, C. (2000). Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice. Infection and Immunity 68, 4765 - 4768. Full article  

Burnett, M. S., Gaydos, C. A., Madico, G. E., Glad, S. M., Paigen, B., Quinn, T. C. et al. (2001). Atherosclerosis in apoE knockout mice infected with multiple pathogens. Journal of Infectious Diseases 183, 226 - 231.

Byrne, G. I. & Kalayoglu, M. V. (1999).  Chlamydia pneumoniae and atherosclerosis: links to the disease process. American Heart Journal 138, S488 - 490.

Byrne, G. I., Skarlotos, S. I., Grunfeld, C., Kalayoglu, M. V., Libby, P., Saikku, P., Summersgill, J. T. & Wyrick, P. (2000). Collaborative multidisciplinary workshop report: interface of lipid metabolism, atherosclerosis, and Chlamydia infection. 

Caligiuri, G., Rottenberg, M., Nicoletti, A., Wigzell, H. &  Hansson, G. K. (2001). Chlamydia pneumoniae infection does not induce or modify atherosclerosis in mice. Circulation 103, 2834 - 2038.

Fong, I. W., Chiu, B., Viira, E., Fong, M. W., Jang, D. & Mahony, J. (1997). Rabbit model for Chlamydia pneumoniae infection. Journal of Clinical Microbiology 35, 48 - 52. Full article  

Fong, I. W., Chiu, B., Viira, E., Jang, D., Fong, M. W., Peeling, R. et al. (1999). Can an antibiotic (macrolide) prevent Chlamydia pneumoniae - induced atherosclerosis in a rabbit model? Clinical and Diagnostic Laboratory Immunology  6, 891 - 694. Full article  

Fong, I. W., Chiu, B., Viira, E., Jang, D. &  Mahony, J. B. (1999). De novo induction of atherosclerosis by Chlamydia pneumoniae in a rabbit model. Infection and Immunity 67, 6048 - 6055. Full article   

Hu, H., Pierce, G. N. & Zhong, G. (1999). The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. Journal of Clinical Investigation 103, 747 - 753. Full article

Kalayoglu M. V. & Byrne, G. I. (1998a). A Chlamydia pneumoniae component that induces macrophage foam cell formation is chlamydial lipopolysaccharide. Infection and Immunity 66, 5067 - 5072. Full article 

Kalayoglu M. V. & Byrne, G. I. (1998b). Induction of macrophage foam cell formation by Chlamydia pneumoniae.
Journal of Infectious Diseases 177, 725 - 729.

Kalayoglu, M. V., Hoerneman, B., LaVerda, D., Morrison, S. G., Morrison, R. P. & Byrne, G. I. (1999a). Cellular oxidation of low-density lipoprotein by Chlamydia pneumoniae. Journal of Infectious Diseases 180, 780 - 790.

Kalayoglu, M. V., Indrawati, Morrison, R. P., Morrison, S. G., Yuan, Y. & Byrne, G. I. (2000). Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions. Journal of Infectious Diseases 181, Suppl 3: S483 - 489.

Kalayoglu, M. V., Miranpuri, G. S., Golenbock, D. T. & Byrne, G. I. (1999b). Characterization of low-density lipoprotein uptake by murine macrophages exposed to Chlamydia pneumoniae. Microbes and Infection 1, 409 - 418.

Laitinen, K., Laurila, A., Pyhala, L., Leinonen, M. &  Saikku, P. (1997). Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits. Infection and Immunity 65, 4832 - 4835. Full article   

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

Muhlestein, J. B., Anderson, J. L., Hammond, E. H., Zhao, L., Trehan, S., Schwobe, E. P. et al. (1998). Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation 97, 633 - 636. Full article   

_{Rust, S., Rosier, M., Funke, H. et al. (1999). Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nature Genetics 22, 352 - 355.}   

Wright, S. D., Burton, C., Hernandez, M., Hassing, H., Montenegro, J., Mundt, S. et al. (2000). Infectious agents are not necessary for murine atherogenesis. Journal of Experimental Medicine 191, 1437 - 1442. Full article

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