Murat V. Kalayoglu
| Years in MSTP | 1994-2000 |
| PhD |
Medical Microbiology and Immunology, 1998 |
| Mentor |
Gerald I. Byrne |
| Thesis |
Interactions Between Chlamydia Pneumoniae and Mononuclear Phagocytes in the Pathogenesis of Atherosclerosis |
| Residency |
Ophthalmology, Harvard University |
| Fellowship |
MBA, MIT Sloan School of Management |
| Investigative Research | Strategies to improve medication adherence |
| Current Position | Practicing ophthalmologist, founder and chief science officer, HealthHonor - A Healthways Company |
Thesis Abstract
Atherosclerosis is a multifactorial disease, and defined risk factors include high serum LDL concentrations, hypertension, and diabetes. However, approximately 40% of all cases of atherosclerosis cannot be associated with defined risk factors. Recent appreciation of atherosclerosis as an inflammatory disease has renewed interest in the role infectious agents may play in lesion initiation and progression.
In particular, the intracellular prokaryotic pathogen Chlamydia pneumoniae has been associated with atherosclerosis by sero-epidemiological studies, detection of the organism from atheromas, isolation and propagation of the organism from atheromas, antibiotic treatment trials and animal studies. Despite an abundance of such clinical associations, however, how the organism may initiate and promote atherosclerosis remains unknown.
The hypothesis examined in the current work is that C. pneumoniae modulates select mononuclear phagocyte M-PHI functions in ways that may contribute to atherosclerosis. In these studies, C. pneumoniae was found to induce M-PHI foam cell formation and LDL oxidation, events directly implicated in lesion development, in the presence of high levels of LDL, a defined risk factor for atherosclerosis. Foam cell formation resulted from excess uptake of native LDL by mechanisms that did not involve the classical Apo B/E LDL-receptor.
Importantly, chlamydial lipopolysaccharide was identified as a C. pneumoniae component that could induce LDL uptake and foam cell formation. In contrast to foam cell formation, cellular LDL oxidation by C. pneumoniae was attributable mainly to the 60 kDa chlamydial heat shock protein (chsp60), an inflammatory antigen recently localized to atheroma macrophages, and occurred by superoxide-independent mechanisms. Studies compiled in this thesis therefore indicate that C. pneumoniae can modulate key functions of the M-PHI and define specific virulence determinants that mediate these events.
These studies underscore the importance of examining putative risk factors for atherosclerosis in the context of defined risk factors such as LDL-cholesterol. Furthermore, these findings suggest novel pathogenic mechanisms for C. pneumoniae in the initiation and progression of atherosclerotic lesions, and may help elucidate a causative role for the pathogen in atherosclerosis.
Thesis Publications
Kalayoglu MV, Galvan C, Mahdi OS, Byrne GI, Mansour S. Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. Arch Ophthalmol 121:478-482, 2003.
Kalayoglu MV, Libby P, Byrne GI. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 288:2724-2731, 2002.
Kalayoglu MV, Galvan CA, Mahdi OS, Byrne GI, Mansour S. Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. Invest Ophthalmol Vis Sci 43:2818, 2002.
Kalayoglu MV, Perkins BN, Byrne GI. Chlamydia pneumoniae-infected monocytes exhibit increased adherence to human aortic endotheial cells. Microbes Infection 3:963-969, 2001.
Byrne GI, Skarlotos SI, Grunfeld C, Kalayoglu MV, Libby P, Saikku P, Summersgill JT, Wyrick P. Collaborative multidisciplinary workshop report: interface of lipid metabolism, atherosclerosis, and Chlamydia infection. J Infect Dis 181:S490-S491, 2000.
Kalayoglu MV, Indrawati, Morrison RP, Morrison SG, Yuan Y, Byrne GI. Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock 60 in macrophage-lipoprotein interaction. J Infect Dis 3:S483-S489, 2000.
Kalayoglu MV, M Myint, Byrne GI. Reply. J Infect Dis 181:1869-1870, 2000.