Is infection with Chlamydia pneumoniae a causative agent in atherosclerosis?

doi:10.1016/S1357-4310(98)01351-3

Molecular Medicine Today

Volume 4, Issue 10, 1 October 1998, Pages 426-430

Molecular Medicine T...

https://doi.org/10.1016/S1357-4310(98)01351-3 Get rights and content

Abstract

There is mounting evidence to suggest that Chlamydia pneumoniae might play a role in atherosclerosis. Serological studies and detection of the microorganism in atheromatous lesions were the first indications of an association between C. pneumoniae and the disease. Studies suggest that anti-chlamydial chemotherapy has a favorable effect on cardiovascular disease in humans. Moreover, infection of animals with C. pneumoniae induces inflammatory changes in the aorta that are suggestive of atherosclerosis and accelerates the progression of existing atherosclerotic lesions. If the pathogenic role of C. pneumoniae in atherosclerosis is defined more conclusively by future studies, the development of preventive or therapeutic measures against infection might provide an effective strategy to reduce the risk of atherosclerosis.

Section snippets

The microorganism and the disease

C. pneumoniae is a human respiratory pathogen[2]that accounts for 5–10% of community-acquired pneumonia, bronchitis and sinusitis. Seventy per cent of infections are asymptomatic or remain limited to non-febrile upper respiratory tract infection. Antibodies against C. pneumoniae are rare in children under 5 years of age, increase rapidly from 5–10 years of age with yearly increases of 6–8%, reach 50% at 20 years of age, and reach 75% in old age. Seroprevalence among adult men is considerably

Association of antibodies against C. pneumoniae and the risk of cardiovascular disease

The association of antibodies or immune complexes against C. pneumoniae with CAD, coronary artery stenosis, carotid artery stenosis, aortic aneurysm and stroke has been well documented by investigators worldwide, mostly in case control studies7, 9. Despite the small sample sizes of these studies, all studies show a statistically significant association between antibody against C. pneumoniae and risk of cardiovascular event, arterial stenosis or stroke gail[with an average odds ratio of 2.0

C. pneumoniae is tropic for cardiovascular tissues

Based on the examination of autopsy tissues by ICC and PCR (Ref. [16]), C. pneumoniae appears to be tropic for cardiovascular tissue because it was found in 21 (55%) of 38 patients examined. Of the patients that tested positive, 52% had the microorganism only in cardiovascular tissues, 33% in cardiovascular and non-cardiovascular tissue, and 14% in non-cardiovascular tissues only (mainly the lungs). The tropism for cardiovascular tissues appears to be specific because the microorganism was not

Proof of an etiological role for C. pneumoniae in atherosclerosis

There are three possible roles for C. pneumoniae in the etiology of atherosclerosis: (1) C. pneumoniae is an innocent bystander, (2) C. pneumoniae might induce atherosclerosis, and (3) C. pneumoniae might accelerate the progression of atherosclerosis.

Two approaches can be taken to answer these questions: therapeutic trials in humans and the use of animal models. Since 1997, preliminary results from these two approaches have been reported that support a role for C. pneumoniae in the etiology of

Concluding remarks

Proof that C. pneumoniae infection is associated with the etiology of atherosclerosis requires the simultaneous use of animal models alongside well-designed human intervention studies. Human trials are complicated by not knowing: (1) which treatment regimens will most efficiently eradicate chronic infection, (2) the most effective age of intervention and (3) how often to treat. The successful treatment of peptic ulcers, long thought to be a disease of non-infectious origin, with antibiotics

Glossary

Angioplasty—Surgery on blood vessels. Balloon angioplasty is often used to reopen a narrowed artery caused by atherosclerosis. It involves the inflation of a balloon delivered to the site of obstruction with a catheter.
Atherosclerosis—Atherosclerosis is a form of arteriosclerosis in which there is fatty degeneration of the middle coat, or intima, of the arterial wall. The disease is characterized by the presence of atheromas—plaques predominantly composed of lipids and cholesterol—in the

The outstanding questions

•
Can an antibiotic therapy be designed that is effective in reducing or ameliorating atherosclerosis and related manifestations?
•
What is the molecular, cellular and immunological basis of C. pneumoniae pathogenesis that contributes to the atherosclerotic process? If defined, do these represent potential targets for prevention or intervention strategies?
•
Can a vaccine be developed to prevent infection and at what age should patients be vaccinated?
•
What diagnostic methods could be used to determine

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Cited by (48)

Antibodies to Chlamydia pneumoniae are Associated with Increased Intima Media Thickness in Asymptomatic Indian Individuals
2009, Journal of Stroke and Cerebrovascular Diseases
Chlamydia pneumoniae has been found to be associated with cerebrovascular and cardiovascular diseases in seroepidemiologic studies. The aim of this study was to investigate whether this organism is associated with increased intima media thickness (IMT) of carotid arteries in asymptomatic individuals. Serum titer of antibodies to C pneumoniae antibodies IgA and IgG in 100 asymptomatic individuals older than 40 years was measured by microimmunofluorescence. These subjects also had their IMT measured by B-mode ultrasound in the common carotid artery on both sides. Comparison of baseline characteristics between the group with abnormal IMT (>0.08 cm) and group having normal IMT (≤0.08 cm) showed significant association of C pneumoniae antibodies and hypertension with the former (i.e., abnormal IMT group). Multiple logistic regression (stepwise method) established C pneumoniae as an independent risk factor for increased IMT. To conclude, this study demonstrated that C pneumoniae infection is associated with an increase of IMT in the common carotid artery.
Chlamydia pneumoniae antibodies in various subtypes of ischemic stroke in Indian patients
2008, Journal of the Neurological Sciences
As infections occur more frequently in developing countries, we carried out this prospective case-control study, to establish the association, if any, between C. pneumoniae antibodies and ischemic stroke particularly in relation to its subtypes.
Antibodies (IgG and IgA) to C. pneumoniae in serum were measured by microimmunofluorescence test in 200 consecutive ischemic stroke patients and 200 age and sex matched controls.
Seventy two out of 200 ischemic stroke patients (36%) had positive C. pneumoniae antibodies (IgG or IgA), compared to 35 out of 200 controls (17.5%) (p < 0.0001). IgG antibody was positive in 64/200 (32%) ischemic stroke patients, compared to 34/200(17%) controls (p < 0.0001) and IgA was positive in 20/200(10%) ischemic stroke patients compared to 1/200(0.5%) controls (p < 0.0001). Logistic regression analysis showed statistically significant association between C. pneumoniae antibody positivity and ischemic stroke, thereby establishing it as an independent risk factor. Prevalence of C. pneumoniae antibodies was significantly higher in all stroke subtypes (except the stroke of undetermined etiology) compared to controls.
Significant and independent association was found between C. pneumoniae antibodies and ischemic stroke in this sample of south Indian population. The association was found in all ischemic stroke subtypes, except stroke of undetermined etiology.
Molecular basis defining human Chlamydia trachomatis tissue tropism: A possible role for tryptophan synthase
2002, Journal of Biological Chemistry
Here we report the cloning and sequencing of a region of the chlamydiae chromosome termed the “plasticity zone” from all the human serovars of C. trachomatis containing the tryptophan biosynthesis genes. Our results show that this region contains orthologues of the tryptophan repressor as well as the α and β subunits of tryptophan synthase. Results from reverse transcription-PCR and Western blot analyses indicate that the trpBA genes are transcribed, and protein products are expressed. The TrpB sequences from all serovars are highly conserved. In comparison with other tryptophan synthase β subunits, the chlamydial TrpB subunit retains all conserved amino acid residues required for β reaction activity. In contrast, the chlamydial TrpA sequences display numerous mutations, which distinguish them from TrpA sequences of all other prokaryotes. All ocular serovars contain a deletion mutation resulting in a truncated TrpA protein, which lacks α reaction activity. The TrpA protein from the genital serovars retains conserved amino acids required for catalysis but has mutated several active site residues involved in substrate binding. Complementation analysis inEscherchia coli strains, with defined mutations in tryptophan biosynthesis, and in vitro enzyme activity data, with cloned TrpB and TrpA proteins, indicate these mutations result in a TrpA protein that is unable to utilize indole glycerol 3-phosphate as substrate. In contrast, the chlamydial TrpB protein can carry out the β reaction, which catalyzes the formation of tryptophan from indole and serine. The activity of the chlamydial Trp B protein differs from that of the well characterized E. coli andSalmonella TrpBs in displaying an absolute requirement for full-length TrpA. Taken together our data indicate that genital, but not ocular, serovars are capable of utilizing exogenous indole for the biosynthesis of tryptophan.
High-density lipoprotein-associated apolipoprotein A-I: The missing link between infection and chronic inflammation?
2002, Autoimmunity Reviews
Citation Excerpt :
The possibility of a persistent antigenic stimulus arising from an infection cannot be confirmed or refuted. A tremendous diversity of pathogens have been involved in ‘inducing’ chronic inflammation, some of them being involved in several diseases, i.e. Chlamydia pneumoniae or seropositivity to Chlamydia pneumoniae was demonstrated in RA, MS and atherosclerosis patients [34–36] and many viruses have also been incriminated [37–39]. Although molecular mimicry was demonstrated for some of these pathogens, no clear-cut link has been established between one particular pathogen and the induction of one specific chronic inflammatory disease.
The etiology of chronic immuno-inflammatory diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and atherosclerosis is far from being elucidated. It is generally accepted that multiple factors are involved in the development of such pathologies, including factors of genetic susceptibility that interact in complex ways with diverse environmental factors, i.e. gender, nutrition, environment, etc. Furthermore, infection has often been pinpointed as playing a causal role. However, no distinctive pattern has yet emerged from the tremendous number of compiled results that would provide a generally acceptable hypothesis of the etiology of immuno-inflammatory diseases, and the possibility of a persistent antigenic stimulus arising from an infection cannot be confirmed or refuted. At the cellular level, chronic inflammation is characterized by the infiltration of immuno-inflammatory cells into the target tissue, which mostly precedes tissue damage. At the inflammatory site, monocytes and T lymphocytes are in close proximity. We have demonstrated that contact-mediated activation of monocytes by stimulated T lymphocytes is a major stimulus triggering the production of large amounts of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) whose importance in chronic inflammation is well known. We recently established that high-density lipolipoprotein (HDL)-associated apolipoprotein (apo) A-I is a specific inhibitor of cytokine production in monocyte-macrophages upon contact with stimulated T cells. HDL-associated apo A-I is a negative acute-phase protein, i.e. a protein whose level is lowered by more than 25% during the acute phase. This review aims at highlighting the fact that HDL-associated apo A-I might play the role of a constitutive anti-inflammatory factor. The decrease of plasma levels of HDL-associated apo A-I upon acute inflammation may be a sign of the possible development of chronic inflammation, i.e. individuals presenting with risk factors might develop chronic inflammatory diseases after infection. We thus hypothesize that HDL-associated apo A-I might be the missing link between infection and chronic inflammation.
Chlamydia pneumoniae infection is not involved in carotid artery stenosis
2002, Atherosclerosis
Recent studies have suggested the existence of a close relationship between Chlamydia pneumoniae infection and atherosclerosis. However, it has been speculated that C. pneumoniae infection is not associated with early atherosclerosis but with advanced atherosclerosis. In the present study, we test this hypothesis. In 524 consecutive patients who underwent cerebral angiography were recruited for the study. From the films obtained during angiography, percent stenosis of neck internal carotid artery was calculated according to the method of the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Serum C. pneumoniae IgG and IgA antibodies were measured by a commercial ELISA enzyme immunoassay kit. Cerebrovascular risk factors such as age, gender, hypertension, diabetes mellitus, hyperlipidemis and smoking were assessed by interview. Old age above 60 years and diabetes mellitus were found to be independent risk factors for carotid artery stenosis in this study after adjustment for cerebrovascular risk factors. When we defined carotid artery stenosis as the presence of greater than 30% stenosis of one artery, there was no association after adjustment for other risk factors between C. pneumoniae IgG and IgA seropositivity and the presence of carotid artery stenosis for any cut-off value of seropositivity. When we defined carotid artery stenosis as the presence of greater than 70%, there was also no association between C. pneumoniae IgG and IgA seropositivity and the presence of carotid artery stenosis for any cut-off value of seropositivity. These results suggest that C. pneumoniae infection is not associated with carotid artery atherosclerosis.
Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice
2001, Atherosclerosis
Cytomegalovirus (CMV) infection has been associated with coronary artery disease, but it is unknown whether the virus can causally contribute to atherogenesis. To determine whether the virus has this capacity, we infected an atherosclerotic-prone mouse strain (C57BL/6J apoE−/−) with murine CMV. At 14 days of age, 30 mice received CMV (30 000 pfu) ip and 30 received virus free media. At 13 and 16 weeks atherosclerotic lesion size was measured from aortic sinus cross-sections. Infection did not alter plasma levels of cholesterol, triglycerides, and high density lipoprotein (HDL); however, 4 weeks after infection IFNγ levels were elevated (infection vs control: 156 ± 49 vs 50 ± 22 pg/ml, P = 0.04). No differences in lesion size were present at 13 weeks post infection. However, by 16 weeks mean aortic sinus lesion area (mm² × 10³ ± SEM; N = 75) in the CMV-infected mice was significantly greater than in uninfected mice (74 ± 6 vs 57 ± 6; P = 0.04). CMV caused the greatest increase (34%) in lesion size in females (103 ± 9 vs 77 ± 10; P = 0.05; N = 35). These results provide additional evidence implicating CMV as a causal agent of atherosclerosis, at least in an animal model.

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¹: MD PhDProfessor of Pathobiology

²: PhDProfessor of Pathobiology

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Is infection with Chlamydia pneumoniae a causative agent in atherosclerosis?

Abstract

Section snippets

The microorganism and the disease

Association of antibodies against C. pneumoniae and the risk of cardiovascular disease

C. pneumoniae is tropic for cardiovascular tissues

Proof of an etiological role for C. pneumoniae in atherosclerosis

Concluding remarks

Glossary

The outstanding questions

Lancet

Lancet

Lancet

The pathogenesis of atherosclerosis: a perspective for the 1990s

Nature

Chlamydia pneumoniae (TWAR)

Clin. Microbiol. Rev.

Cytomegalovirus and atherosclerosis

BioEssays

Virus-induced atherosclerosis

J. Exp. Med.

Virus in the etiology of atherosclerosis

Proc. Natl. Acad. Sci. U. S. A.

Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy

New Engl. J. Med.

Chlamydia pneumoniae and cardiovascular disease

Cardiologia

Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries

J. Infect. Dis.

Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15–34 years old)

Proc. Natl. Acad. Sci. U. S. A.

Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group

Ann. Intern. Med.