Human epidemiological studies have shown an association between periodontal and vascular diseases. In parallel, the inflammatory -and potentially infectious- nature of atherosclerosis is gaining recognition, suggesting a potential link between infectious diseases, such as periodontitis, and atherosclerosis. However, the effect of periodontal pathogens in atherosclerosis has not been clearly established. The goal of this proposal is to investigate the contribution of oral pathogens to the development of atherosclerotic lesions in a murine model. The apolipoprotein E knockout mouse (ApoE) prone to atherosclerosis will be infected with one recognized human periodontal pathogen in an established model of chronic and localized infection (subcutaneous chamber). Experimental conditions (including power calculations) have been optimized in preliminary studies using this model of infection-enhanced atherosclerosis.
Aim 1 will focus on answering the question """"""""could periodontal pathogens contribute to the development of atherosclerotic lesion?"""""""" Localized infection will be established by intra-chamber injection of live bacterial cultures of Porphyromonas gingivalis in pre-immunized ApoE mice. Controls will receive medium alone. Two strains of P. gingivalis with varying virulence properties will be tested for their ability to induce an increase in the aorta atheroma lesion size (evaluated at sacrifice by histomorphometry). In parallel, the inflammatory response will be monitored by measuring levels of serum inflammatory cytokines (IL-6 and IL-1 by ELISA) and acute phase proteins (Serum Amyloid A by ELISA). Interaction analyses will be performed to test our hypothesis that infection with P. gingivalis contributes to the development of atherosclerotic lesion by triggering an inflammatory and acute phase response.
Aim 2 will address the question """"""""what specific virulence trait(s) expressed by P. gingivalis contribute to the development of atherosclerotic lesion?"""""""" Mutants of P. gingivalis for specific virulence factors (Pep0 and FimA,) will be prepared in the most atherogenic strain identified in aim 1 in laboratories. These mutants will be tested in our murine model in regard to atheroma lesion size. In addition, presence of P. gingivalis DNA will be investigated by PCR in descending aorta and liver samples, and serum anti-P. gingivalis antibody levels will be measured by ELISA, to test our hypothesis that specific virulence traits confer to P. gingivalis the ability to evade the host antibody defense system, and reside in organs such as the aorta and the liver. Results from these studies will help in the identification of new targets for atherosclerosis and vascular disease therapies.
|Champagne, C; Yoshinari, N; Oetjen, J A et al. (2009) Gender differences in systemic inflammation and atheroma formation following Porphyromonas gingivalis infection in heterozygous apolipoprotein E-deficient mice. J Periodontal Res 44:569-77|