Jpn. J. Infect. Dis., 52, 223‑227, 1999

Invited Minireview
Chlamydia pneumoniae and Atherosclerosis
Kazunobu Ouchi *Department of Pediatrics, Saiseikai Shimonoseki General Hospital,

Klbne‑cho 3‑4‑1 , Shimonoseki, Yamaguchi 751 ‑8502, Japan(Received November 29, I 999)

CONTENTS:
1. Introduction

2. Seroepidemiological studies
3. Demonstration of Chlamydia pneumoniae in atheroscleroticand non‑atherosclerotic tissues
4. 1n vitro infection model

5. Animalinfection model
6. Antimicrobialprevention of secondary cardiac events
7･ Pathogenesis

8. Genome project
9. Conclusion

StJMMARY: Chlamydia pneumoniae is the third species of the genus Chlamydia and has been known to cause
respiratory tract infections. Since the association betweenthe seropositivity of C. pneumoniae and ischemic heartdiseases was reported in I 988, the association between C. pneumoniae and atherosclerosis has been noteworthy･

Positive findings of the association between C. pneumoniae and atherosclerosis have been reported asthe resultof seroepidemiologiCalsurveys, histological studies to detect C. pneumoniae in humanatherosclerotic tissues,
and animal infection models. These data supported that C. pneumoniae infection occurs in human vascular walls
and may accelerate the foam cell formation of macrophage and smooth muscle cells, and may play a causativerole in atherosclerosis. Severallarge‑scale studies of the antimicrobial prevention of secondary cardiac events
are in progress. The genome projects for C. pneumoniae have recently been reported. A number of issues remain
unclear, however, and further intensive research is necessary.

factors. We need to find another risk factors such as C.

1. Introduction

pneumoniae. In this paper, I review recent reportsthat demon‑

Chlamydia is a small intracellular energy parasite of hoststrated this association.

cells and has aunique life cycle betweenanelementary bodyand a reticulated b∝ly. Chlamydia is different from a virus

2. Sennpidemiological sttldies

because it has both DNA and RNA and is sensitive to anti一

microbial agents. Three species inthe genus Chlamydia are

C. pneumoniae infection is a very common disease at any

known to cause humaninfections. Chhmydia tTlaChonw's causes

age. Seropositive rates against C･ pneumoniae in adult aretrachoma, sexually transmitted diseases, neonatal conJunC‑
tivitiS, and infantile pneumonia. Chlamydia psittaci causes

over 50% and reach to around 80% in older populations allover the world (3,4). Atherosclerosis is also a very common

psittacosis. Chlamydia pneumoniae is the third species of thedisease in older people, so it seems to us to be very difficult

genus Chlamydia and has been known to cause respiratory

to find the association between C. pneumoniae infection andtract infections such as pharyngitis, bronchitis, and atypicalatherosclerosis. However, odds ratios of the seropositivity topneumonia since 1985 (1). Since Saikku et al. (2) reported

C･ pneumoniae in atherosclerotic diseases such as ischemic

the association betweenthe seropositivity of C. pneumoniae
and ischemic heart diseases in 1 988, the association between

heart disease, stroke,and hypertension were almostthe same,around 2.,0 (I.6‑4.4) in many populalions in the world (2,5‑this unlque bacteria and atherosclerosis has received a great17). These positive findings were reported in more than 20

deal of attention. Although there are many well‑known risk

papers published in English joumals, while only two papers

reported negative relation ( 18, 19)･ Althoughalmostall of thesefactors such as smoking, hypertension, diabetes mellitus,

studies were carried out in westem countries, Miyashita etal. (14) have recently reportedthe same positive association

hyperlipidemia, and so on, more than 30% of patients withacute myocardial infarction do not have any known risk

in Japan.

*Corresponding author: Tel:+81 ‑832‑3 1 ‑5201 , Fax: +81 ‑832‑321
3. Demonstration of C. pneumoniae in atherosclerotic

8209, E‑mail: outi(氾@tip･ne.Jp

and non‑atherosclerotic tissues

ThisarticleisanInvitedMimireviewbasedonalecturepresented
atthe9thSymposlumOftheNationalInstituteofInfectious
Diseases,Tokyo,21May1999.

Since Shor et al. (20) reported the presence of C･
pneumoniae in atherosclerotic tissues of the coronary arterybyanelectron microscopy, many researchers have succeeded223in demonstrating C. pneumoniae by immunohistochemistry,

microbial treatment and for evaluating the C. pneumoniae‑

polymerase chain reaction, and isolation in culture (2ト35).

specific response to the treatment?

The positive rates of C. pneumoniae in atherosclerotic tissuesiv) Do macrolideantibiotics prevent secondary cardiac attackby acting agalnSt bacteria other than C･ pneumoniae or by

Vary, but average approximately 60% (range 33‑73%), includ‑

acting mechanisms other thananti‑C. pneumoniae activity?

lng Ours (25,26)･ These positive findings were appeared in

more than 20 reports published in English joumals, while

Several large‑scale studies have recently begun in westemonly two published papers reported that no C. pneumoniae

countries to answer the question i). In ACES (Azithromycin

was found in atherosclerotic tissues ( 18,36). So far, Only three

for Prevention of Cardiac Endpoints Study) sponsored by NIH

groups succeeded in isolating C. pneumoniae by cell culture,
although many researchers have attempted･ Two groups

to paticipate in this study. Patients in the treated group will

isolated only one strain, while Maass et al. (35) isolated 1 1

take azithromycln Weekly for I yearand be monitored regard‑

strains (16%) out of 70 atherosclerotic plaques by more than
10 passages, and concluded that the presence of viable C.

The results will appear in 2003. 1f azithromycln Can prevent

pneumoniae in atherosclerotic tissues is a common phenomenon.

secondary cardiac events, we will obtain another tool for

C. pneumoniae was also found in non‑atherosclerotic tissues;

pI℃Venting one of the most common causes of human mortality

the positive rate, however, was quite low (37).

in developed countries.

in USA, 4,(Xのpatients withischemic heart disease are expectedlngthe incidence of cardiac events for the followlng 4 years･

4. Invitro infection model

7. Pathogenesis

The natural hosts of C. pneumoniae are originally tx31ieved to

There is little data about the pathogenesis of C･ pneumoniae

tx the epithelialcells of the humanrespiratory tract. However,infection in either respiratory tract infection or in humanrecent in vitro data have shown that C. pneumoniae alsoatherosclerosis. Although the method fわr establishing clones

infects macrophages, vascular endothelial cells, and smoothof C. pneumoniae has been reported, We cannot yet produce

muscle cells, which are the main players in humanatheroscle‑

stable recombinant mutants of C. pneumoniae. Chlamydial

rosis (38‑41 ). C. pneumoniae increased cholesterol accumula‑heat shock protein and antigen‑mimicity have recently been

tions in infected macrophages (42,43). These data supported

targeted (32,52). To confirmthe role of these mechanisms inthat C･ pneumoniae infection might ∝cur in human vascular

the pathogenesis of C. pneumoniae, we need to develop awalls and accelerate the foam cell formation of macrophages

reliable method for establishing stable recombinant mutants.

and smooth muscle cells.

Further intensive research in this field is necessary.

5.Animal infection model

S. Genome project

So far two animalmodels were used to examinethe associa‑
tion tx:tween C. pneumoniae infection and atherosclerosis. One

pneumoniae. One is the US group of Universityof Califomia,

Two groups independently finished genome projects of C･

a New Zealand White rabbit (46‑49). Several researchers

Berkeley, and used the strain CWL029 isolated from apatientwithacute pneumomia in AtIanta (53). The other is theisanApoE‑deficient transgenic mouse (44,45) and the otherindependently reported that C. pneumoniae was found inJapanese group of Yamaguchi University School of Medicine

atherosclerotic tissues at the initial stage of atherosclerosis

and so on, which used the strain ∫‑ 1 38 isolated from a patient

after intranasalinnoculation of C. pneumoniae tothese micewith pneumonia in Shimonoseki (54). The genome sizes ofand rabbits. Atherosclerosis was accelerated by intranasal
infection,andthen progression of atherosclerosis was inhibited

CWL‑029 and ∫‑138 are 1,230,230 bp and 1,226,570 bp,

bythe early use of antibiotics. These data supported thethat the nucleotide sequence identity was 96‑ 100% and the
deduced amino acid sequence identity was 88‑ 100% between

respectively. A comparative study of the two strains revealedcausative role of C. pneumoniae in atherosclerosis in theseanimals･ Howeverthe more appropriate animal model, suchthe two strains. Generally speaking, the identification of genes

as non‑human pnmates, should be developed.

of the two strainsis highly similar;there were, however, somedifferences inthe pmp, transporter,and glucose metabolism‑
related genes. These data fromthe genome projects will

6･Antimicrobial prevention of secondary cardiac events

contribute to elucidate the pathogenesis of C. pneumoniae

If C. pneumoniae plays a causative role in atherosclerosis

and provide a possible tool fわr preventing and treating C･

in humans,antibiotics may have a favorable effect in patientspneumoniae infection, such as antimicrobialagentsand vaccines･
Severalresearch institutesand companies have already started

with atherosclerosis, and prevent the secondary attack ofischemic heart disease･ Two groups independently reported

to develop vaccines to C. pneumoniae by uslngthe data ofthat macrolideantibiotics significantly reduced the seeondary

the genome projects.

cardiac attacks in patients with unstable anglna Or ln malesurvivors of myuardial infarction, although the number of

9. Conclusion

patients studied inthese reports were very small (50,51).
Further researchesare requested in order toanswer the follow‑

Only 10 years have passed since the association between

C. pneumoniae and atherosclerosis was first reported. Manythings remain unclear. The odds ratios between hepatitis B
antigen seropositivityand hepatic cancer were more than 1 00,

lng questions;i) Can macrolide antibiotics really reduce the incidence of
secondary cardiac attacks, even in patients with a low risk ofcardiac attacks?

while the ∝lds ratios tx:tween C. pneumoniae seropositivityandii) What is the optimal dose and duration of antimicrobial

coronary artery diseases were approximately 2‑4･ Therefore, it

treatment?

is very diWICult to confirm based only on the ser∝pidemiologicaliii) What is a reliable marker fわr selecting patients fわr antト

data that C. pneumoniae plays a causative or accelerating role224

in the development of atherosclerosis. We need further informa‑

12. Dahlen, G. T., Boman, J., Brigander, L S. and Lindblom,tion in addition to the detection of this organism in atheroI

B･(1995): Lp(a) 1iIX)protein, IgG, IgA,and lgManti仙ies

sclerotic tissues, animalinfection models, and antimicrobial

to Chlamydia pneumoniae and HLA class II genotype1nprevention of secondary cardiac events. We can use the whole

early coronary artery disease. Athrosclerosis, I 14, 165‑

genome information from two strains isolated in the US
and Japan. However, in order to determine the role of C.

13. Miettinen, H., Lehto, S., Saikku, P., Haffner, S. M.,

174.

pneumoniae inthe pathogenesis of atherosclerosis by uslng

Rornemaa, T., Pyorala, K.and h血bo, M.(1996):AsS∝ia‑

the genome information, we need to develop a method fortion of Chlamydia pneumoniae and acute coronary heart

clonlng Stable recombinant mutants of C･ pneumoniae･ We

disease events in non‑insuline dependent diabeticand
non‑diabetic subjects in Finland. Eur. Heart J., 17, 682‑

need further intensive researches in the future.

688.

14. Miyashita, N., Toyota, E., Sawayama, T., Matsumoto,A., Mikami, Y., Kawai, N., Takeda, K., Niki, Y. andMatsushima, T. ( 1 998): Association of chronic infection

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