Antigens and proteomics.

Chlamydial heat shock proteins


Heat shock proteins (hsps) are a family of closely related proteins, widely distributed in virtually all organisms, including chlamydiae and humans. Hsps from these widely different sources show remarkable structural similarity [amino acid sequence homology] of the order of 40% or more [Amberger et al., 1997]. Chlamydiae are no exception, with the main chlamydial heat shock proteins showing homology with human mitochondrial proteins cpn10, hsp60 or hsp70.

By definition, hsp expression is increased as a result of exposure of an organism to stress and expression is regulated by an HRCA - CIRCE represser operator pair [ Wilson & Tan, 2002]. Relevant stresses are particularly likely to occur in inflamed or damaged tissue. Typical stresses might result from exposure to elevated temperature (fever); protein degradation (by enzymes from inflammatory cells); mechanical stress (as in coronary artery linings exposed to haemodynamic forces) or chemical stress (such as chlamydiae exposed within a phagocytic cell to superoxide or other active oxygen radicals). As "chaperone" proteins they are concerned with the intracellular folding and refolding, assembly and translocation of proteins, particularly those damaged by stress [van Eden et al., 1998]. At the cellular level they can block chlamydial apoptosis and can rescue host proteins from stress-related damage by facilitating their energy-dependent renaturation and refolding [Hightower, 1991].

Relationship to auto-immune and chronic disease.

Bacterial hsps are highly stimulatory to the immune system despite their relatedness to host hsp.They have been implicated with auto-immune diseases, where, essentially, the host immune system attacks its own tissues. Auto-immune responses to self-hsp have been detected in patients with juvenile chronic arthritis and diabetes [van Eden et al., 1998] and in atherosclerosis [Amberger et al., 1997]. Rats injected with an extract of tubercle bacteria develop auto-immune arthritis, giving rise to the concept that immune responses to microbial heat shock proteins might trigger an auto-immune response against structurally related human heat shock protein [van Eden et al., 1998]. This, the theory suggests, might be central to some chronic inflammatory diseases.

Interest in the possible involvement of chlamydial hsps in the pathogenesis of chronic chlamydial infection was first stimulated by observations that application of a detergent extract of the Chlamydophila caviae guinea pig inclusion conjunctivitis (GPIC) agent to the eyes of previously infected guinea pigs, stimulated the local infiltration of inflammatory mononuclear cells [Morrison et al., 1989]. Mononuclear cells are one of the hallmarks of chronic inflammation. The resulting theory was that, in chronically or repeatedly infected individuals, increased chlamydial hsp expression secondary to the action of gamma interferon produced by the T-helper 1 cell mediated immune response might drive persistent infection and chronic inflammation [Beatty et al., 1994]. Chronic infection might in turn lead to the inflammation and repair characteristic of the severe sequelae of C. trachomatis infection. These observations may be criticised on the following grounds: 1. In the guinea pig model, neither the pannus nor conjunctival scarring characteristics of chronic human ocular infection (trachoma) were observed. 2. The chlamydial hsp60 preparation used contained detergent and was relatively crude. 3. The guinea pig is an animal unusually prone to developing delayed hypersensitivity type responses. However, there are some, largely circumstantial, data to support a role for chlamydial hsp in severe disease. Evidence has already been presented that repeated infection is more likely to lead to severe disease (see Immunopathogenesis.RepeatedInfections). Mice previously sensitised by immunization with either a crude extract of C. mridarium or with hsp [Blander & Amortegui, 1994] suffered more severe inflammation when subsequently challenged intravaginally with live organisms.

Antibody responses to chlamydial and human hsp.

A considerable number of studies [see: Ward, 1999] have shown an association between antibodies to chlamydial hsp and the chronic sequelae of chlamydial infection. In one study of 129 women with verified pelvic inflammatory disease (PID), approximately half of the patients with antibodies to human hsp60 had antibodies cross reactive with chlamydial hsp [Domeika et al., 1998; see Human_Infections/Pathogenesis of PID]. However this does not prove that autoimmune responses necessarily play a significant role in the immunopathogenesis of PID. Antibodies might be a proxy for cell mediated immune responses. Alternatively, antibody responses to chlamydial-specific or human-reactive components on chlamydial hsp might simply arise by chance as a result of long term exposure to chlamydial infection.

This criticism has been addressed in a study of a Gambian community with endemic trachoma, where antibodies to chlamydial hsp60 were found in significantly more (32%) individuals with conjunctival scarring than in those without clinical signs of disease (16%; p<.001). This was still the case after correcting for the raised antibody to whole chlamydiae generally [Peeling et al., 1998].

Finally, Huittinen et al., 2002 report that elevated IgA antibody to human hsp is associated with an increased risk of coronary artery disease, particularly if it is also associated with the inflammation marker C-reactive protein and with C. pneumoniae infection.

See also: Growth cycle regulation

[MEW] February 2003

See also: Molecular Biology of GroEL


<a name="#hsp_refs"></a> Amberger, A., Maczek, C., Jurgens, G., Michaelis D, Schett G, Trieb K, Eberl T, Jindal S, Xu Q, Wick G.
(1997). Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidised low-density lipoproteins. Cell Stress & Chaperones, 2, 94-103.

Beatty, W. L., Byrne, G. I., & Morrison, R. P. (1994). Repeated and persistent infection with Chlamydia and the development of chronic inflammation and disease. Trends in Microbiol. 2, 94-98.

Blander, S. J. & Amortegui, A. J. (1994). Mice immunized with a chlamydial extract have no increase in early protective immunity despite increased inflammation following genital-infection by the mouse pneumonitis agent of C. trachomatis. Infect. Immun. 67, 3617-3624.

Domeika, M., Domeika, K., Paavonen, J., Mardh, P. A. & Witkin, S. S. (1998). Humoral immune response to conserved epitopes of Chlamydia trachomatis and human 60-kDa heat-shock protein in women with pelvic inflammatory disease. Journal of Infectious Diseases, 177, 714 - 719.

van Eden, W., van der Zee, R., Alberta, G. A., Prakken, B. J., Wendling, U., Anderton, S. M. & Wauben, M. H. (1998). Do heat shock proteins control the balance of T-cell regulation in inflammatory diseases? Immunol.Today, 19, 303-307.

Hightower, L. E. (1991). Heat shock, stress proteins, chaperones and proteotoxicity. Cell, 56, 191-197.

Huittinen, T., Leinonen, M., Tenkanen, L., Manttari, M., Virkkunen, H., Pitkanen, T., Wahlstrom, E., Palosuo, T., Manninen, V. & Saikku, P. (2002). Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae infection, and inflammation in predicting coronary risk. Arteriosclerosis Thrombosis and Vascular Biology 22, 431 437.

Morrison, R. P., Lyng, K., & Caldwell, H. D. (1989). Chlamydial disease pathogenesis - ocular hypersensitivity elicited by a genus-specific 57 kDa protein. Journal of Experimental Medicine 169, 663 - 675.

Peeling, R. W., Bailey, R. L., Conway, D, J., Holland, M. J., Campbell, A. E., Jallow, O., Whittle, H. C. & Mabey DC. (1998). Antibody response to the 60 kDa heat shock protein is associated with scarring trachoma. Journal of Infectious Diseases 177, 256 - 262.

Viale, A. M., Arakaki, A. K., Soncini, F. C. & Ferrey, R. A. (1994). Evolutionary relationships among eubacterial groups as inferred from GroEL (chaperonin) sequence comparisons. International Journal of Systematic Bacteriology 44, 527-533.

Ward, M. E. (1999). Mechanisms of Chlamydia-induced disease. Pages 171-210. In: (Stephens, R. S. ed.) Chlamydia. Intracellular biology, pathogenesis and immunity. ASM Press, Washington D.C. ISBN 1-55581-155 - 8.

Wilson AC, Tan M. (2002). Functional analysis of the heat shock regulator HrcA of Chlamydia trachomatis. Journal of Bacteriology 184, 6566 - 6571.

See also: Molecular biology of GroEL.

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