Authors:Giovenale Moirano & Federico Vitiello
C.Pneumoniae In the Pathogenesis of Atherosclerosis
Cardiovascular disease is the leading cause of morbidity and mortality in industrialized countries, and its incidence is increasing rapidly in less-developed nations .
The major pathological process underlying cardiovascular events in different vascular beds is atherosclerosis, a chronic systemic arterial inflammatory disease leading to stenosis of the artery and many other complications.
(In 2011, coronary athersclerosis was one of the top ten most expensive conditions seen during inpatient hospitalizations in the U.S., with aggregate inpatient hospital costs of $10.4 billion)
Wikipedia 2014
C.Pneumoniae
Chlamydophila pneumoniae is a species of Chlamydophila, an obligate intracellular bacterium that infects humans and is a major cause of pneumonia.
It has a biphasic life-cycle existing as either an EB (elementary body) or a RB (reticulate body). The EB is the extracellular infectious non-replicating form which, when internalized by a susceptible cell, differentiates into the metabolically active RB. The RB replicates, by binary fission, forming an intracellular microcolony (inclusion) and then re-differentiates, after 48–72 h, back into EB forms, which are released from the infected cell to begin another infection cycle. Under certain conditions, RBs do not re-differentiate directly into EBs, but form interim non-replicating persistent bodies, allowing the bacterium to maintain a chronic latent infection
Wikipedia 2014
The presence of C pneumoniae in atheroma has been detected by serology by using specific antibodies against C pneumoniae, including immunoglobulin (Ig) G, IgM, and IgA and confirmed by immunohistochemistry polymerase chain reaction (PCR) Southern hybridization, in situ hybridization, electron microscopy, and electron-microscopic immunohistochemistry.
C.Pneumoniae and vascular disease:un update 2006
There is some evidence to suggest that C. pneumoniae could play a role in all stages of atherosclerosis, from the initial inflammatory lesion to plaque rupture.
C. pneumoniae gains access to the vasculature during local inflammation of the lower respiratory tract, when the organism is disseminated around the body in blood mononuclear cells.
C. pneumoniae can infect vascular ECs (endothelial cells) in vitro, stimulating the secretion of pro-inflammatory cytokines like TNFa IFNg and IL-6 and the expression of leucocyte adhesion molecules, which results in adhesion and trans-endothelial migration of leucocytes, inflammation within the vessel wall and the initial ‘response to injury’ initiating lesion formation.
Formation of foam cells, the hallmark of early atherosclerotic lesions (fatty streaks), is the result of the uptake of oxLDL into macrophages.
Macrophages are central mediators of the inflammatory atheromatous lesion .
Macrophages cultured in the presence of native LDL do not accumulate lipids to become foam cells. This is because the native LDL receptor is tightly regulated by intracellular free cholesterol content ; receptor-mediated endocytosis of LDL and subsequent extraction of its cholesterol lead to transcriptional down-regulation of LDL receptors. These regulatory mechanisms have been proposed to maintain a homeostatic level of intracellular cholesterol .
However, macrophages infected with C. pneumoniae cannot regulate intracellular cholesterol content and accumulate excess levels of exogenous lipids.
C. pneumoniae exposure can induce macrophages to take up increased amounts of native LDL and become foam cells, possibly due to up-regulation of LDLrs.
C. pneumoniae induces foam cell formation not only by promoting lipoprotein binding and entry but also by interfering with the macrophage's cholesterol efflux machinery.
If C. pneumoniae dysregulates cholesterol efflux regulatory proteins such as ABC1, then the pathogen could dysregulate cellular cholesterol homeostasis by enhancing lipoprotein entry, down-regulating lipid efflux, or by a combination of both mechanisms.
Oxidized LDL promotes the mitogenic actions of Chlamydia pneumoniae in vascular smooth muscle cells 2011
In addition, chlamydial LPS (lipopolysaccharide) and cHsp60 (chlamydial heat-shock protein 60) can induce oxidation of LDL within the neointima,oxLDL can be taken up by unregulated scavenger receptors providing a mechanism by which C. pneumoniae could enhance foam cell formation.
Furthermore C Pneumoniae can lead to vascular wall inflammation expressing high level of cHSPs 60.
HSPs(Heat shock protein) belong to a family of approximately two dozen proteins that are important in regulating the molecular response to the vessel wall under both normal and stressed conditions. HSPs are highly conserved across species, and their expression in vascular tissues can be triggered by several different stimuli.Upregulation of HSPs is mediated by heat shock transcription factors binding to the regulatory elements of the HSP gene promoters.
HHSPs(human HSP) are expressed in abundance by cells under stress in the vessel wall like in the atherosclerotic lesion.A persistent Chlamydia infection is accompanied by an increased production of cHSP60(Chlamydia HSP) because the bacterium secretes high level of this protein.
Since HSP is an important and very immunogenic antigen pratically al human develop humoral and cellular immunity against this antigen as consequences of infection.
This protective immune reaction can lead to cross reactivity with autologous HSP60 that can for example be expressed by endotelial cells.
Antigenic mimicry and chronic immunostimulation in the vascular wall can lead to the release of local and systemic cascades of inflammatory cytokines.
Acute Chlamydia pneumoniae infection with heat-shock-protein-60-related response in patients with acute coronary syndrome. 2005
Heat Shock Proteins: Pathogenic Role in Atherosclerosis and Potential Therapeutic Implications 2012
C. pneumoniae-infected ECs can secrete growth factors which, together with cytokines and growth factors from infected macrophages and oxLDL, stimulate Smooth Muscolar Cells proliferation and migration from the media to the intima.
Endothelial cells have been shown to secrete several soluble factors, such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor 1 (IGF-1) , which are important in SMC migration and proliferation during atherogenesis.
As show below the production of soluble factor(s) by HUVEC ( Human umbelical vein endotelial cells) cultures infected with C. pneumoniae.
SMCs secrete extracellular matrix molecules, such as fibrin, proteoglycans and collagen, which contribute to the formation of a fibrous cap; in this way, C. pneumoniae infection in the vascular wall could contribute to fibrofatty plaque formation
Plaque destabilization, rupture and thrombus formation may also be influenced by C. pneumoniae infection. cHsp60 stimulates macrophages to produce MMPs (matrix metalloproteinases) , which weaken the plaque, and the up-regulation of tissue factor and PAI-1 (plasminogen activator inhibitor-1) by infected ECs and SMCs increases the likelihood of thrombosis in the event of plaque rupture
Chlamydia species infect human vascular endothelial cells and induce procoagulant activity 1997
Role of C.Pneumoniae and atherosclerosis 2008
Clinical Implications
Treatment trials of antibiotics for the prevention of untoward cardiovascular events in animal models of atherosclerosis have produced results that were sufficiently encouraging to inspire multiple, small-scale secondary prevention trials in patients.
In the Randomised Trial of Roxithromycin in non–Q-wave Coronary Syndromes (ROXIS) trial, in which 202 patients with unstable angina or non–Q-wave MI were randomly assigned placebo or roxithromycin treatment (150 mg twice daily for 30 days), roxithromycin significantly reduced the incidence of recurrent angina, MI, and death ≤31 days of the start of treatment.
The final report of the study showed that patients still had reduced rates of death and reinfarction for at least 6 months after treatment with roxithromycin.
In 2005, Grayston et al published the results of the Azithromycin and Coronary Event Study (ACES) trial sponsored by the National Institutes of Health. In this randomized, multicenter, prospective trial, 4012 patients with documented stable coronary artery disease received either 600 mg of azithromycin or placebo weekly for 1 year. Mean follow-up was 3.9 years.
At 1 year, no significant risk reduction was noted in the azithromycin group with regard to the primary end points, which was a composite of death due to coronary heart disease, nonfatal MI, coronary revascularization, or hospitalization for unstable angina.
Azithromycin treatment also did not significantly reduce the risk of stroke or of death from any cause.
Similar findings were reported by Cannon et al who performed a double-blind, randomized, placebo-controlled trial of long-term fluoroquinolone therapy in patients with acute coronary syndrome. At 2 years, the primary end point event,a composite of death from all causes, MI, documented unstable angina requiring rehospitalization, revascularization , and stroke—had occurred in 23.7% of the gatifloxacin patients and 25.1% of the placebo patients (P = .41).
These results show the need for better understanding of the pathogenic mechanisms of C pneumonia in order to target specific Chlamydia antigens and design trials with new effective antibiotic regimens.
Clinical Trial 2003
Conclusions
For the past 20 years, numerous studies have evaluated the role and importance of C.pneumoniae in atherosclerosis, but it is a major challenge to either prove or disprove a causal role for a common agent in a highly prevalent disease.
Seroepidemiological studies indicate an association between infection and cardiovascular events, and histopathological evidence confirms that.
C. pneumoniae is capable of persistently infecting atherosclerotic plaques in humans.
The strongest evidence that C. pneumoniae is sufficient to initiate atherosclerosis and contributes to progression and plaque instability comes from experiments in rabbits and mice. Trials of antimicrobial therapy have overall been disappointing, but, in view important limitations in study design and execution, these results cannot rule out an important pathogenic role.
Considering the totality of present evidence,C.pneumoniae is neither alone sufficient nor is it necessary to cause atherosclerosis or its clinical consequences in humans.
However, C. pneumoniae is highly likely to be a modifiable risk factor that may be amenable to future therapies focused on either eradication (antibiotic therapy or early immunization) or modifying the vascular inflammatory response to infection.
Future clinical studies will be necessary to define the importance of this risk across a range of populations.
