C. pneumoniae and possible mechanisms of coronary artery disease
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 the evidence for some of the suggested mechanisms by which C. pneumoniae might cause coronary artery disease.
[Caveat emptor: The following takes a set of individual experimental observations and puts them together, out of context, to show that there are plausible mechanisms by which C. pneumoniae might exacerbate heart disease. Some of the foundations on which this "construction" is based, for example the role of chlamydial heat shock protein in chronic disease, are tenets of chlamydial faith rather than certainties. Likewise it is likely that other bacteria also have a role. At the end of the day, the crucial test is not the beauty of the potential mechanisms, insightful though they may be, but whether it is possible to demonstrate significant benefits to public health by the targeted use of antibiotic for coronary artery disease].
Portal of entry. [See: C. pneumoniae pneumonia]. As already reviewed, C. pneumoniae is a common agent of lower respiratory tract infection, involving the alveolar air sacs where it is likely to be ingested by alveolar macrophages. Access from the lung to the circulation is relatively easy as only a single cell separates the alveolar air sac from the circulation. C. pneumoniae may be transported across the cellular barrier either as free particles or, more likely, carried within macrophages which are actively migrating across the endothelium . Chlamydial replication in matured human macrophages is probably limited [Airenne et al., 1998] but the organism might be transferred to CD3+ T lymphocytes during antigen processing.
Dissemination in the blood. A major study of 1300 patients demonstrated that C. pneumoniae circulates in the blood stream within mononuclear cells [Wong et al., 1999], subsequently identified as CD3+ T lymphocytes [Kaul et al., 2000].
Adhesion to vessel walls and entry. In coronary artery disease, C. pneumoniae is associated with monocytes potentially capable of adherence to vessel walls. This is uncommon in normal blood donors [Kaul et al., 2000]. C. pneumoniae infected monocytes show enhanced adhesion to aortic endothelial cells [Kalayoglu et al., 2001]. At sites of active atheroma , inflammatory cytokines, and chlamydial infection of endothelia will lead to the upregulation of vascular adhesion factors, including E-selectin, ICAM-1, and VCAM-1 [Kaukoranta-Tolvanen et al., 1996a; see also Cytokine Induction].
Infection and dysfunction of endothelial cells. Monocyte cell lines can transmit C. pneumoniae infection to coronary artery endothelial cells in cell culture [Gaydos, 2000]. Indeed, C. pneumoniae is capable of infecting all the cell types typically associated with atheroma, including aortic artery smooth muscle cells [Gaydos et al., 1996; Godzik et al., 1995; Kaukoranta-Tolvanen et al., 1996b]. C. pneumoniae infection of endothelia impairs the latter's ability to induce nitric oxide-mediated arterial relaxation [Liuba et al., 2000] perhaps by inducing cyclooxygenase-dependent vaso-constrictors. Endothelial dysfunction is observed in both resistance and epicardial coronary vessels [Liuba et al., 2003]. C. pneumoniae infection of endothelia also promotes the transendothelial migration of inflammatory cells [Molestina et al., 1999], the production of inflammatory mediators [Summersgill et al., 2000] and induction of pro-coagulant activity [Fryer et al., 1997] and of platelet derived growth factor B [Coombes et al., 2002].
Proliferation of smooth muscle cells and thickening of the aortic intima characteristic of atheroma may be stimulated in part by C. pneumoniae-triggered production of platelet derived growth factor B [Coombes et al., 2002].
Atherogenesis. Atheroma is increasingly recognised as involving inflammatory stimuli. 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: Cytokine Induction]. 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]. Chlamydiae in any case interfere with the normal intracellular trafficking of lipid and membranes within cells [see: Membrane Traffic]. Chlamydial LPS is thought to be a major trigger of chlamydial-induced LDL uptake [Kalayoglu & Byrne, 1998a]. For a useful review see Kalayoglu et al., 2002.
Cell mediated immune responses to chlamydial heat shock protein in plaque. Chsp60 has been identified within human atheromatous tissue and in aortic valve stenosis [Skowasch et al., 2003], is both immunogenic and pro-inflammatory and is thought to be associated with the immunopathology of chlamydial disease [Kalayoglu et al., 2000 see: Heat Shock Proteins] including the gamma interferon-induced production of IFNg. Chsp60 can activate the cellular immune response through the CD14 monocyte receptor for bacterial lipopolysaccharide [Kol et al., 2000]. Chsp60 promotes matrix metalloproteinase and cytokine production by monocytes. It also promotes cytokine production by 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]. Chlamydial heat shock protein [chsp60] also induced monocyte LDL oxidation in a dose dependent manner, whereas another chlamydial heat shock protein, chsp10, did not [Kalayoglu et al., 1999a; 2000].
Plaque rupture. Chlamydial induced activation of matrix metalloproteases among other factors [Kol et al., 1998] may lead to plaque destabilisation and premature rupture. This in turn may give rise to myocardial infarction. At present there is very little experimental evidence for this other than the observed but probably confounded association of C. pneumoniae antibody with myocardial infarction [see: C. pneumoniae serological evidence].
[MEW] August 2003.
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