Periodontal diseases are among the most common chronic polymicrobial infections of mankind and a substantial amount of epidemiological data is accumulating linking periodontal disease with increased risk for cardiovascular events in humans. Several studies have detected the presence of periodontal bacterial genomic DNA (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Aggregator actinomycetemcomitans, Campylobacter rectus, Prevotella intermedia, Fusobacterium nucleatum, and Eikenella corrodens) in atherosclerotic lesions of aortic tissue, coronary vessels, and carotid artery. Many of the atherosclerotic coronary artery samples contained more than one type of periodontal bacterial genomic DNA. Similarly, few in vivo studies have shown that the predominant pathogen P. gingivalis can accelerate atherosclerosis in mouse model. Our major objective is to examine additional periodontal disease pathogens such as T. denticola, T. forsythia, and F. nucleatum for their ability to accelerate atherosclerosis with P. gingivalis as polymicrobial infection. The general premise is that several different oral bacteria cause periodontal disease and that perhaps it is a combination of these pathogens that synergistically induce atherosclerosis. Although atherosclerotic cardiovascular disease is almost certainly a multifactorial disease, there is now strong and increasing evidence that infection and inflammation represent important risk factors. Inflammation plays a central and continuous role in the pathogenesis of atherosclerosis from its initiation to the development of clinical complications, specifically heart attacks, strokes, and peripheral vascular occlusion. Furthermore, Toll-like receptors (TLRs) 1, 2, 4, and 5 distinguish between different molecular patterns specific to pathogens and activate a rapid innate immune response. Recent evidence that TLRs activation contributes to the development and progression of atherosclerosis, has come from genetic and clinical studies mechanistically linking TLRs, inflammation, and atherosclerosis. Elevated TLR expression in inflamed gingival tissues suggests that excess inflammation mediated by TLRs is a driving factor in periodontal disease. However, there is no direct evidence for an infectious bacterial etiology of individual species (except P. gingivalis) or bacterial consortia in the sequential accumulation of these pathogens in atheromatous plaque. The specific hypothesis of this proposal is that periodontal pathogens that infect the periodontal tissue can infect vascular tissue and induce atherosclerotic plaque formation.
Specific Aim 1 will investigate the synergistic role of periodontal pathogens in the induction of periodontal disease and atherosclerosis in the ApoE-/- mouse model of chronic systemic inflammation.
SPECIFIC AIM 2 will investigate whether TLR2 and TLR4 have a role in pathogen-mediated periodontal disease and associated atherosclerosis in the mouse models with defined TLR genetic deficiency. The Goals are to define the infectious etiology and pathogenesis of atherosclerosis and will enable a rational approach for intervention in atherosclerosis.
Periodontal disease is a chronic inflammatory disease and several periodontal bacterial genomic DNA were detected in atherosclerosis plaque from aorta, carotid, and coronary arteries in humans. There is strong clinical and epidemiological association between periodontal disease and cardiovascular disease.
|Singhrao, Sim K; Harding, Alice; Simmons, Tal et al. (2014) Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer's disease. J Alzheimers Dis 42:723-37|
|Chukkapalli, Sasanka S; Rivera, Mercedes F; Velsko, Irina M et al. (2014) Invasion of oral and aortic tissues by oral spirochete Treponema denticola in ApoE(-/-) mice causally links periodontal disease and atherosclerosis. Infect Immun 82:1959-67|
|Velsko, Irina M; Chukkapalli, Sasanka S; Rivera, Mercedes F et al. (2014) Active invasion of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis and atherosclerosis. PLoS One 9:e97811|
|Lucas, Alexandra R; Verma, Raj K; Dai, Erbin et al. (2014) Myxomavirus anti-inflammatory chemokine binding protein reduces the increased plaque growth induced by chronic Porphyromonas gingivalis oral infection after balloon angioplasty aortic injury in mice. PLoS One 9:e111353|
|Rivera, Mercedes F; Lee, Ju-Youn; Aneja, Monika et al. (2013) Polymicrobial infection with major periodontal pathogens induced periodontal disease and aortic atherosclerosis in hyperlipidemic ApoE(null) mice. PLoS One 8:e57178|