C. pneumoniae Infection in Atherosclerosis
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
C. pneumoniae Infection in Atherosclerosis

Atherosclerosis, the pathological basis of CAD (Coronary Artery Disease) and Ischemic Stroke, is the commonest cause of death and disability in the western world. Atherosclerosis is a multifactorial, highly complex disease with numerous aetiologies simultaneously and sequentially collaborating in subtle ways to affect lesion development, progression and maturation to an advanced, disease-provoking entity (Ref.1). The lesion, or Atheroma, is an inflammatory site composed of a necrotic lipid-rich core, modified vascular endothelium, SMCs (Smooth Muscle Cells), foamy macrophages, lymphocytes and a variety of inflammatory mediators. Inflammation is the key event in Atherosclerotic Plaque fissuring and rupture, causing adverse clinical events. A variety of risk factors are known to be associated with the pathogenesis of Atherosclerosis. These include genetic and lifestyle factors such as Hypercholesterolaemia, High Blood Pressure, Hypoglycaemia, Stress, Smoking, Obesity etc. These traditional risk factors clearly contribute to this CVD (Cardiovascular Disease), but roughly 40% of cases have no well-defined risk factor associated with them. Recent appreciation of Atherosclerosis as a chronic inflammatory disease has rejuvenated efforts to examine the role played by infectious agents in Atherosclerosis. Both Viruses, (for example, HSV (Herpes Simplex Virus), CMV (Cytomegalovirus), Hepatitis-A virus and Influenza virus) and Bacteria, (for example, Chlamydia pneumoniae, Helicobacter pylori, Poryphromonas gingivalis and Mycoplasma species) have been implicated in the progression of the disease. However, only two of these organisms, CMV and C. pneumoniae have attracted serious consideration (Ref.2). Considerable attention has been focused on C. pneumoniae because of its association with Atherosclerosis in conjunction with other traditional risk factors, as evidenced by a variety of epidemiological and experiment-based studies (Ref.3).

Atheroscerosis starts when the very inner lining of the artery (the Endothelium) is damaged, largely due to a reaction to a chronic, fibroproliferative inflammatory stimulation, and oxidative damage to the subendothelial layer (Intima) of the artery. C. pneumoniae is involved in Atherosclerosis by inducing inflammation as well as LDL(Low Density Lipoprotein) oxidation which lead to tissue destruction, repair and fibrosis (Ref.4). Furthermore, C. pneumoniae infection has the capacity to induce and propagate chronic inflammation mediated by Cytokines and Chemokines as well as thrombotic events that contribute to Atherosclerosis. The pathogen infects and multiplies within all cell types commonly found in the Atheroma, including coronary artery Endothelial cells, Macrophages and Aortic Artery SMCs. C. pneumoniae can gain access to the vasculature during local infections, for example, involving the lower respiratory tract and continues its Life Cycle in the Alveolar Macrophages and Monocytes. These infected Leukocytes (specifically Monocytes) serve to disseminate an infection from the lung to other susceptible tissues including Arteries, as infected human Monocytes exhibit increased adherence to human Aortic Endothelial cells. The pathogens are endocytosed by Alveloar Monocytes in the lung of the infected individual in the form of EBs (Elementary Bodies) arranged in a vesicle-like structure, known as Chlamydial Inclusion. The EBs differentiate to form RBs (Reticulate Bodies), which replicate to produce a mature Inclusion (Ref.5). Formation of Inclusions upregulates expression of ligands on the cell surface of Monocytes, in order to facilitate Arterial Endothelium attachment (Ref.2). Specifically, C. pneumoniae upregulates the expression of Alpha2-Integrins on the surface of Monocytes, which facilitate attachment of these cells to the Endothelium. In the Arteries, C. pneumoniae modulates cell biology to trigger inflammatory cascades, release MMPs (Matrix Metalloproteinases) and procoagulant factors, recruit specific T-Cell responses, alter cellular lipid metabolism, promote SMC proliferation, induce endothelial leukocyte adhesion molecule expression, and impair arterial relaxation (Ref.1).

The infected Monocyte with the included RBs adheres to the Arterial Endothelium and migrates between adjacent Endothelial cells into the Intima. In the Intima, the RBs re-differentiate into EBs. Completion of re-differentiation of the RBs in the Inclusion releases infectious EBs, which allows chronic infection within the Intima. The EBs thus released, infect other cell types in the Intima, including resident Macrophages, which upregulate LDL uptake and oxidation to become cholesterol-filled Foam Cells - the hallmark of early lesions in Atherosclerosis (Ref.4). Foam cells are Macrophages that are loaded with engulfed fatty globules-which give the appearance of foam. C. pneumoniae-induced Foam cell formation is mediated chiefly by LPS (Lipopolysaccharide), whereas lipoprotein oxidation occurs mainly by the Chlamydial protein, HSP60 (Heat Shock Protein-60). These two chlamydial components also mediate inflammatory changes such as immunomodulator secretion and receptor upregulation. Moreover, cHSP60 can activate a panel of proinflammatory functions of Atheroma-associated cells which may impair a proper immune response of cells to bacteria in the Atherosclerotic lesions (Ref.6). Infection of macrophages induces production of MMPs and expression of TF (Tissue Factor), which leads to plaque destabilization and thrombus formation, an event that can result in Myocardial Infarction.  Infected human macrophages secrete enhanced levels of inflammatory cytokines such as TNF-Alpha (Tumor Necrosis Factor-Alpha), IL-1Beta (Interleukin-1Beta), IL-6, MCP1 (Monocyte Chemoattractant Protein-1), MIP1Alpha (Macrophage Inflammatory Protein-1Alpha), IL-12 (which promotes lesion progression), and IL-10 (that may prevent apoptosis to perpetuate inflammation). Cytokines released from macrophages and foam cells further upregulate endothelial-cell-adhesion molecule expression that recruits additional leukocytes to the lesions. In an attempt to heal the inflammation, smooth-muscle cells migrate into the Intima, then proliferate and secrete Collagen, Elastin and Proteoglycans to form a fibrous matrix. The mature Atheromatous plaque consists of a fibrous cap comprising variable numbers of smooth muscle cells, macrophages and ECM (Extracellular Matrix), which encapsulates an acellular, lipid-rich necrotic core that is derived, in part, from dead foam cells. Although advanced lesions can impede blood flow, Myocardial Infarctions and strokes result from an acute occlusion that is due to the formation of a thrombus, which forms in response to rupture or erosion of the plaques (Ref.2).

Chronic endothelial infection is the most important factor that has the ability to cause endothelial cell damage and trigger the onset of human Atherosclerosis. Infection of arterial endothelial cells by EBs of C. pneumoniae leads to production of VCAM1 (Vascular-Cell-Adhesion Molecule-1), ICAM1 (Intracellular-Adhesion Molecule-1), P-Selectin, ESel (E-Selectin), TF (Tissue Factor), PAI1 (Plasminogen Activator Inhibitor-1) IL-6 and IL-8 (Ref.4). The expression of adhesion molecules and Chemokines promote leucocyte adherence, migration and intimal inflammation. The expression of the procoagulant Tissue Factor and PAI1 help in modulation of procoagulant activity. C. pneumoniae infection of human endothelial cells also stimulates transendothelial migration of inflammatory cells and triggers secretion of inflammatory mediators (Ref.7). Smooth-muscle cells are also infected by the EBs, which stimulates proliferation. Smooth muscle cells respond to endothelial infection by proliferating, and direct infection of these cells induces secretion of cytokines such as IL-6 and bFGF(Basic Fibroblast Growth Factor) that may alter Atheroma biology by inducing inflammation. Thus, the infection of Monocytes, Macrophages, Endothelial cells and SMCs by C. pneumoniae results in the release of proinflammatory Cytokines-all of which could contribute to the chronic inflammatory response and the enhancement of lesion development  (Ref.1). C. pneumoniae triggers specific cell-mediated immunity within plaques, as evidenced by the detection of C. pneumoniae -specific T lymphocytes in atherosclerotic lesions. These cells appear to be primarily CD4+ Th1 subtypes and may contribute to plaque destabilization by T-Cell Cytokine production. Ifn-Gamma (Interferon-Gamma) produced locally by these T-lymphocytes may prime Atheroma cells to harbor persistent infection with C. pneumoniae (Ref.3).

The clinical manifestations of Atherosclerosis include CAD, Stroke, Abdominal Aortic Aneurysm and peripheral vascular disease. Atherosclerosis may be present for years without causing symptoms. This slow disease process can begin in childhood. In some people, the condition can cause symptoms by the time they reach their 30s. In others, they do not have symptoms until they reach their 50s or 60s. But, as the blockage gets worse, the slowed blood supply to the heart may begin to cause something called Angina Pectoris, i.e, "strangling in the chest", manifested by suffocating, or burning feeling in their chest. The pain is usually experienced when the heart has an extra demand for blood. The recognition of Atherosclerosis as an inflammatory disease in its genesis, progression and ultimate clinical manifestations has created an interesting area of vascular research (Ref.2). The association of C. pneumoniae and Atherosclerosis has paved the way to the prospect of a new treatment in the form of Antibiotics, for the management of Atherosclerotic vascular disease. The efficacy of a wide range of antimicrobial agents, including macrolides, tetracyclines, and quinolones, which target either protein or DNA synthesis of C. pneumoniae, are being tried on animal models. However, the insidious nature of C. pneumoniae infection makes prevention very difficult, and the development of anti-Chlamydial vaccines remains an important goal for researchers (Ref.8).