The Choice of an Appropriate Animal Species in the Study of Chlamydia Pneumoniae as an Atherogenic Agent

  • Satoru Hirono
  • Grant N. Pierce
Part of the Progress in Experimental Cardiology book series (PREC, volume 8)


Different animal models have been used to increase our understanding of the mechanisms responsible for atherosclerosis. We have used the same animal models to study the relationship of atherosclerosis to infection. The data generated from these studies have yielded valuable insights into the mechanisms whereby an infectious agent like Chlamydia pneumoniae augments the atherosclerotic process. The appropriate choice of the optimal animal species in which to study these interactions is critical. This review discusses some of the choices facing the researcher in this field and some of the interesting data that has been gen-erated using the different animal species.

Key words

Atherosclerosis Infection Inflammation Cholesterol Virus Bacteria Atherogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Danesh J, Collins R, Peto R. 1997. Chronic infections and coronary heart disease: is there a link? Lancet 350:430–436.PubMedCrossRefGoogle Scholar
  2. 2.
    Grayston JT. 2000. Background and current knowledge of Chlamydia pneumoniae and atherosclerosis. J Infect Dis 181 (Suppl 3):S402–410.PubMedCrossRefGoogle Scholar
  3. 3.
    Gaydos CA and Quinn TC. 2000. The role of Chlamydia pneumoniae in cardiovascular disease. Advances in Internal Medicine 45:139–173.PubMedGoogle Scholar
  4. 4.
    Muhlestein JB, Anderson JL, Carlquist JF, Salunkhe K, Horne BD, Pearson RR, Bunch TJ, Allen A, Trehan S, Nielson C. 2000. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease-primary clinical results of the ACADEMIC study. Circulation 102:1755–1760.PubMedCrossRefGoogle Scholar
  5. 5.
    Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B. 1999. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes: the final report of the ROXIS study. Eur Heart J 20:121–127.PubMedCrossRefGoogle Scholar
  6. 6.
    Dunne M. 1999. WIZARD and the design of trials for secondary prevention of atherosclerosis with antibiotics. Am Heart J 138:S542–544.PubMedCrossRefGoogle Scholar
  7. 7.
    Grayston JT, Jackson LA, Kennedy WJ, Kronmal RA. 1999. Secondary prevention trials for coronary artery disease with antibiotic treatment for Chlamydia pneumoniae: design issues. Am Heart J 138:S545–S549.PubMedCrossRefGoogle Scholar
  8. 8.
    Jackson LA. 2000. Description and status of the azithrimycin and coronary events study (ACES). J Infect Dis 181(Suppl 3):S579–581.PubMedCrossRefGoogle Scholar
  9. 9.
    Saikku P, Laitinen K, Leinonen M. 1998. Animal model of Chlamydia pneumoniae infection. Athero-sclerosis 140(Suppl 1):S17–19.Google Scholar
  10. 10.
    Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. 1985. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57:65–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. 1993. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 92:883–893.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang SH, Reddick RL, Piedrahita JA, Maeda N. 1992. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468–471.Google Scholar
  13. 13.
    Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. 1992. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. 1994. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140.PubMedCrossRefGoogle Scholar
  15. 15.
    Breslow JL. 1996. Mouse models of atherosclerosis. Science 272:685–688.PubMedCrossRefGoogle Scholar
  16. 16.
    Moghadasian MH, Frohlich JJ, McManus BM. 2001. Advances in experimental dyslipidemia and atherosclerosis. Lab Invest 81:1173–1183.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang ZP, Kuo CC, Grayston JT. 1993. A mouse model of Chlamydia pneumoniae strain TWAR pneumonitis. Infect Immun 61:2037–2040.PubMedGoogle Scholar
  18. 18.
    Kaukoranta-Tolvanen SSE, Laurila AL, Saikku P, Leinonen M, Liesirova L, Laitinen K. 1993. Experimental infection of Chlamydia pneumoniae in mice. Microb Pathog 15:293–302.PubMedCrossRefGoogle Scholar
  19. 19.
    Yang ZP, Kuo CC, Grayston JT. 1995. Systemic dissemination of Chlamydia pneumoniae following intranasal inoculation in mice. J Infect Dis 171:736–738.PubMedCrossRefGoogle Scholar
  20. 20.
    Moazed TC, Kuo CC, Grayston JT, Campbell LA. 1997. Murine models of Chlamydia pneumoniae infection and atherosclerosis. J Infect Dis 175:883–890.PubMedCrossRefGoogle Scholar
  21. 21.
    Hu H, Pierce GN, Zhong G. 1999. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J Clin Invest 103:747–753.PubMedCrossRefGoogle Scholar
  22. 22.
    Moazed TC, Kuo CC, Grayston JT, Campbell LA. 1998. Evidence of systemic dissemination of Chlamydia pneumoniae via macrophages in the mouse. J Infect Dis 177:1322–1325.PubMedCrossRefGoogle Scholar
  23. 23.
    Kuo CC, Grayston JT, Campbell LA, Goo YA, Wissler RW, Benditt EP. 1995. Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15–34 years old). Proc Natl Acad Sci USA 92:6911–6914.PubMedCrossRefGoogle Scholar
  24. 24.
    Jackson LA, Campbell LA, Schmidt RA, Kuo CC, Cappuccio AL, Lee MJ, Grayston JT. 1997. Specificity of detection of Chlamydia pneumoniae in cardiovascular atheroma-evaluation of the innocent bystander hypothesis. Am J Pathol 150:1785–1790.PubMedGoogle Scholar
  25. 25.
    Yamashita K, Ouchi K, Shirai M, Gondo T, Nakazawa T, Ito H. 1998. Distribution of Chlamydia pneumoniae infection in the atherosclerotic carotid artery. Stroke 29:773–778.PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor-Robinson D. 1998. Chlamydia pneumoniae in vascular tissue. Atherosclerosis 140(Suppl 1): S21–S24.PubMedCrossRefGoogle Scholar
  27. 27.
    Moazed TC, Campbell LA, Rosenfeld ME, Grayston JT, Kuo CC. 1999. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. J Infect Dis 180;238–241.PubMedCrossRefGoogle Scholar
  28. 28.
    Rothstein NM, Quinn TC, Madico G, Gaydos CA, Lowenstein CJ. 2001. Effect of azithromycin on murine arteriosclerosis exacerbated by Chlamydia pneumoniae. J Infect Dis 183:232–238.PubMedCrossRefGoogle Scholar
  29. 29.
    Ramirez JA. 1996. Isolation of Chlamydia pneumoniae from coronary artery of a patients with coronary atherosclerosis. Chlamydia pneumoniae/Atherosclerosis Study Group. Ann Intern Med 125:979–982.PubMedGoogle Scholar
  30. 30.
    Caligiuri G, Rottenberg M, Nicoletti A,Wigzell H, Hansson GK. 2001. Chlamydia pneumoniae infection does not induce or modify atherosclerosis in mice. Circulation 103:2834–2838Google Scholar
  31. 31.
    Ekman MR, Grayston JT, Visakorpi R, Kleemola M, Kuo CC, Saikku P. 1993. An epidemic of infection due to Chlamydiae pneumonia in military conscripts. Clin Infect Dis 17:420–425.PubMedCrossRefGoogle Scholar
  32. 32.
    Aalto-Setala K, Laitinen K, Erkkila L, Leinonen M, Jauhiainen M, Ehnholm C, Tamminen M, Puolakkainen M, Penttila I, Saikku P. 2001. Chlamydia pneumoniae does not increase atherosclerosis in the aortic root of apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 21:578–584.PubMedCrossRefGoogle Scholar
  33. 33.
    Paigen B, Holmes PA, Mitchell D, Albee D. 1987. Comparison of atherosclerotic lesions and HDL- lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. Atherosclerosis 64:215–221.PubMedCrossRefGoogle Scholar
  34. 34.
    Burnett MS, Gaydos CA, Madico GE, Glad SM, Paigen B, Quinn TC, Epstein SE. 2001. Athero-sclerosis in apo E knockout mice infected with multiple pathogens. J Infect Dis 183:226–231.PubMedCrossRefGoogle Scholar
  35. 35.
    Nigg C and Eaton MD. 1944. Isolation from normal mice of a pneumotropic virus which forms elementary bodies. I Exp Med 79:497–510.CrossRefGoogle Scholar
  36. 36.
    Blessing E, Nagano S, Campbell LA, Rosenfeld ME, Kuo CC. 2000. Effect of Chlamydia trachomatis infection on atherosclerosis in apolopoprotein E-deficient mice. Infect Immun 68:7195–7197.PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell LA, Blessing E, Rosenfeld M, Lin TM, Kuo CC, 2000. Mouse models of C. pneumoniae infection and Atherosclerosis. J Infect Dis 181(suppl 3);S508–513.PubMedCrossRefGoogle Scholar
  38. 38.
    Blessing E, Lin T, Campbell LA, Rosenfeld ME, Lloyd D, Kuo CC. 2000. Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice. Infect Immun 68:4765–4768.PubMedCrossRefGoogle Scholar
  39. 39.
    Blessing E, Campbell LA, Rosenfeld ME, Chough N, Kuo CC. 2001. Chlamydia pneumoniae infection accelerates hyperlipidemia induced atherosclerotic lesion development in C57BL/6J mice. Atherosclerosis 158:13–17.PubMedCrossRefGoogle Scholar
  40. 40.
    Kalayoglu MV, Miranpuri GS, Golenbock DT, Byrne GI. 1999. Characterization of low-density lipoprotein uptake by murine macrophages exposed to Chlamydia pneumoniae, Microb Infect 1:409–418.CrossRefGoogle Scholar
  41. 41.
    Kalayoglu MV and Byrne GI. 1998. A Chlamydia pneumoniae component that induces macrophage foam cell formation is chlamydial lipopolysaccharide. Infect Immun 66:5067–5072.PubMedGoogle Scholar
  42. 42.
    Lopes-Virella M, Klein R, Stevenson H. 1987. Low density lipoprotein metabolism in human macrophages stimulated with microbial or microbial-related products. Arteriosclerosis 7:176–184.PubMedCrossRefGoogle Scholar
  43. 43.
    Funk J, Feingold K, Moser A, Grunfeld C. 1993. Lipopolysaccaride stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation. Atherosclerosis 98:67–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu L, Hu H, Ji H, Murdin AD, Pierce GN, Zhong G. 2000. Chlamydia pneumoniae infection significantly exacerbates aortic atherosclerosis in an LDLR-/- mouse model within six months. Mol Cell Biochem 215:123–128.PubMedCrossRefGoogle Scholar
  45. 45.
    Laitinen K, Laurila A, Pyhala L, Leinonen M, Saikku P. 1997. Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits. Infect Immun 65:4832–4835.PubMedGoogle Scholar
  46. 46.
    Fong IW, Chiu B, Viira E, Fong MW, Jang D, Mahony J. 1997. Rabbit model for Chlamydia pneumoniae infection. J Clin Microbiol 35:48–52.PubMedGoogle Scholar
  47. 47.
    Fong IW, Chiu B, Viira E, Jang D, Mahony JB. 1999. De novo induction of atherosclerosis by Chlamydia pneumoniae in a rabbit model. Infect Immun 67:6048–6055.PubMedGoogle Scholar
  48. 48.
    Muhlestein JB, Anderson JL, Hammond EH, Zhao L, Trehan S, Schwobe EP, Carlquist JF. 1998. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation 97:633–636PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Satoru Hirono
    • 1
  • Grant N. Pierce
    • 1
  1. 1.Division of Stroke and Vascular Disease, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of MedicineUniversity of ManitobaWinnipegCanada

Personalised recommendations