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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE020820-02
Application #
8230484
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2011-03-01
Project End
2016-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$366,250
Indirect Cost
$116,250
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Chukkapalli, Sasanka; Rivera-Kweh, Mercedes; Gehlot, Prashasnika et al. (2016) Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice. Arthritis Res Ther 18:161
Chukkapalli, S S; Velsko, I M; Rivera-Kweh, M F et al. (2016) Global TLR2 and 4 deficiency in mice impacts bone resorption, inflammatory markers and atherosclerosis to polymicrobial infection. Mol Oral Microbiol :
Singhrao, Sim K; Harding, Alice; Chukkapalli, Sasanka et al. (2016) Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease. J Alzheimers Dis 51:935-48
Chukkapalli, Sasanka S; Rivera-Kweh, Mercedes F; Velsko, Irina M et al. (2015) Chronic oral infection with major periodontal bacteria Tannerella forsythia modulates systemic atherosclerosis risk factors and inflammatory markers. Pathog Dis 73:
Gangula, Pandu; Ravella, Kalpana; Chukkapalli, Sasanka et al. (2015) Polybacterial Periodontal Pathogens Alter Vascular and Gut BH4/nNOS/NRF2-Phase II Enzyme Expression. PLoS One 10:e0129885
Velsko, Irina M; Chukkapalli, Sasanka S; Rivera-Kweh, Mercedes F et al. (2015) Periodontal pathogens invade gingiva and aortic adventitia and elicit inflammasome activation in αvβ6 integrin-deficient mice. Infect Immun 83:4582-93
Poole, Sophie; Singhrao, Sim K; Chukkapalli, Sasanka et al. (2015) Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis 43:67-80
Velsko, Irina M; Chukkapalli, Sasanka S; Rivera-Kweh, Mercedes F et al. (2015) Fusobacterium nucleatum Alters Atherosclerosis Risk Factors and Enhances Inflammatory Markers with an Atheroprotective Immune Response in ApoE(null) Mice. PLoS One 10:e0129795
Singhrao, Sim K; Harding, Alice; Poole, Sophie et al. (2015) Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer's Disease. Mediators Inflamm 2015:137357
Chukkapalli, Sasanka S; Velsko, Irina M; Rivera-Kweh, Mercedes F et al. (2015) Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice. PLoS One 10:e0143291

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