Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

Background— Infectious diseases have emerged as potential risk factors for cardiovascular disease (CVD). Epidemiological studies support a connection between periodontal disease, a chronic inflammatory disease of the supporting tissues of the teeth, and CVD. Methods and Results— To directly test the connection between periodontal disease and atherosclerosis, apoE −/− mice were orally challenged with the periodontal disease pathogen Porphyromonas gingivalis or an invasion-impaired P gingivalis fimbriae-deficient mutant (FimA−). Both wild-type P gingivalis and the FimA− mutant were detected in blood and aortic arch tissue of apoE −/− mice by PCR after challenge. ApoE −/− mice challenged with wild-type P gingivalis presented with increased atherosclerotic plaque and expressed the innate immune response markers Toll-like receptor (TLR)-2 and TLR-4 in aortic tissue. Despite detection of the FimA− mutant in the blood and in aortic arch tissue, apoE −/− mice challenged with the FimA− mutant did not present with periodontal disease, upregulation of TLRs, or accelerated atherosclerosis. Furthermore, we demonstrate that immunization to control P gingivalis -elicited periodontal disease concomitantly prevents P gingivalis -accelerated atherosclerosis. Conclusions— We conclude that invasive P gingivalis accelerates atherosclerosis.

Mechanisms of Periodontitis - Induced Atherosclerosis

“…In many epidemiological studies, periodontitis was proven to play important roles in initiation and progression of CVD, [69,70] by chronic infection on the blood vessels [20][21][22][23][24][25][26][27][28][29] or by the elevation of body�s CRP level. [29][30][31][32][33][34][35][36][37][38][39] The prevalence of chronic periodontitis was very high among populations, especially in chronic form.…”

“…[75] Chronic infection was known to be able to cause endothelial dysfunction. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] PG�s fimbriae secretes protein, called gp130, [83] which facilitate PG to invade EC and trigger celluler immune response. [84] The host will secrete TNF, [85] IL-1, IL-6, IL-10, and IL-12 [86][87][88] by TLR�s stimulation.…”

“…[84] The host will secrete TNF, [85] IL-1, IL-6, IL-10, and IL-12 [86][87][88] by TLR�s stimulation. [26,85,[88][89][90] TLR is part of immune system, which will respond to PAMP. [91] Protein in PG�s fimbriae may act as PAMP which triggers immune response by activating TLR, which, hence stimulate the host to produce cytokines.…”

“…[19,20] Atherosclerosis had been proven to be induced by periodontopathogen from periodontitis. [21][22][23][24][25][26][27][28] Inflammation in mouth may cause systemic inflammation, which is indicated by the elevation of CRP in the body, [29,30] which is functioned as markers, [31,32] predictors of CVD, [33,34] and may induce atherosclerosis lesions. [35][36][37][38] Focal infection in mouth may induce atherosclerosis lesions by initiate systemic and humoral immune responses.…”

Is Porphyromonas gingivalis Cell Invasion Required for Atherogenesis? Pharmacotherapeutic Implications

“…Porphyromonas gingivalis, which has been strongly associated with adult periodontitis, is a Gram-negative, nonmotile, obligate anaerobe that can invade and infect epithelium, endothelium, and vascular smooth muscle cells (6 -9) and appears to alter endothelial function (10). The capacity for invasion and the subsequent inflammatory responses is in part mediated by fimbriae (11)(12)(13), and the virulence of P. gingivalis may vary among individual strains depending on which one of the five major types of FimA gene they possess (14).…”