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Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE Mice.

Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Zheng D, Lucas AR, Kesavalu L - PLoS ONE (2015)

Bottom Line: Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis.Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES.In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.

ABSTRACT
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

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Polybacterial infection significantly increased atherosclerotic plaque growth in the ascending aorta and the aortic root.(A). Total plaque area of infected mice was elevated at both 12- and 24 weeks of infection, but was significant compared to controls at 24 weeks of infection (p < 0.05). (B). Intimal/medial layer thickness ratio of infected mice was increased relative to sham-infected mice at both 12- and 24 weeks of infection, although not significant (p = 0.1599 and 0.1339). (C). CD3+ T cell counts were significantly higher in 24 week–infected mice than sham-infected mice. (D). H & E stained aortic section illustrates large plaques in infected mice. (E). H & E stained aortic section showing small plaques in sham-infected mice. (F). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (20X magnification). (G). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (200X magnification). (H). Aortic section from sham-infected mice devoid of infiltrating CD3+ T cells. Black arrow heads indicate atherosclerotic plaque. Red arrows indicate infiltrated CD3+ T cells. L—artery lumen, I—intimal layer, M—medial layer, A—adventitial layer. * p < 0.05.
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pone.0143291.g005: Polybacterial infection significantly increased atherosclerotic plaque growth in the ascending aorta and the aortic root.(A). Total plaque area of infected mice was elevated at both 12- and 24 weeks of infection, but was significant compared to controls at 24 weeks of infection (p < 0.05). (B). Intimal/medial layer thickness ratio of infected mice was increased relative to sham-infected mice at both 12- and 24 weeks of infection, although not significant (p = 0.1599 and 0.1339). (C). CD3+ T cell counts were significantly higher in 24 week–infected mice than sham-infected mice. (D). H & E stained aortic section illustrates large plaques in infected mice. (E). H & E stained aortic section showing small plaques in sham-infected mice. (F). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (20X magnification). (G). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (200X magnification). (H). Aortic section from sham-infected mice devoid of infiltrating CD3+ T cells. Black arrow heads indicate atherosclerotic plaque. Red arrows indicate infiltrated CD3+ T cells. L—artery lumen, I—intimal layer, M—medial layer, A—adventitial layer. * p < 0.05.

Mentions: In order to determine the extent of polymicrobial infection-induced atherosclerotic plaque development, atherosclerotic plaque was measured in sections cut from the aortic root at the level of the valves to the abdominal aorta in infected and sham-infected mice (n = 6, both groups). Minimal plaque was detected in the thoracic and abdominal aorta as has been previously reported, however, plaque was detected in the aortic root and ascending aorta and plaque growth was compared for polymicrobial and non-infected animals at 12 and 24 weeks follow up. Plaque areas as well as intimal and medial thickness were measured, and the intimal thickness / medial thickness ratios were calculated for 12 and 24 week-infected mice. Mice at 12 weeks of infection had larger plaque areas than sham-infected mice, but this did not achieve statistical significance (Fig 5A). In contrast, at 24 weeks infected mice developed significantly increased plaque area (p < 0.05) on comparison to sham-infected mice at 24 weeks as well as when compared to 12 week-infected mice. By 24 weeks of infection, intimal / medial layer thickness ratios also demonstrated a trend toward increased plaque thickness in infected mice when compared to sham-infected mice which was not significant (p = 0.1339) Fig 5B and 5D–5E). Twenty four-weeks-infected mice had significantly (p = 0.0003) increased CD3+ T cell counts per high power field (100X HPF) in the intimal layer (Fig 5C and 5F–5G) when compared to the sham-infected mice (Fig 5H).


Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE Mice.

Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Zheng D, Lucas AR, Kesavalu L - PLoS ONE (2015)

Polybacterial infection significantly increased atherosclerotic plaque growth in the ascending aorta and the aortic root.(A). Total plaque area of infected mice was elevated at both 12- and 24 weeks of infection, but was significant compared to controls at 24 weeks of infection (p < 0.05). (B). Intimal/medial layer thickness ratio of infected mice was increased relative to sham-infected mice at both 12- and 24 weeks of infection, although not significant (p = 0.1599 and 0.1339). (C). CD3+ T cell counts were significantly higher in 24 week–infected mice than sham-infected mice. (D). H & E stained aortic section illustrates large plaques in infected mice. (E). H & E stained aortic section showing small plaques in sham-infected mice. (F). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (20X magnification). (G). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (200X magnification). (H). Aortic section from sham-infected mice devoid of infiltrating CD3+ T cells. Black arrow heads indicate atherosclerotic plaque. Red arrows indicate infiltrated CD3+ T cells. L—artery lumen, I—intimal layer, M—medial layer, A—adventitial layer. * p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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pone.0143291.g005: Polybacterial infection significantly increased atherosclerotic plaque growth in the ascending aorta and the aortic root.(A). Total plaque area of infected mice was elevated at both 12- and 24 weeks of infection, but was significant compared to controls at 24 weeks of infection (p < 0.05). (B). Intimal/medial layer thickness ratio of infected mice was increased relative to sham-infected mice at both 12- and 24 weeks of infection, although not significant (p = 0.1599 and 0.1339). (C). CD3+ T cell counts were significantly higher in 24 week–infected mice than sham-infected mice. (D). H & E stained aortic section illustrates large plaques in infected mice. (E). H & E stained aortic section showing small plaques in sham-infected mice. (F). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (20X magnification). (G). Aortic Sections demonstrating numerous CD3+ T cells in 24-week polybacterial-infected mouse (200X magnification). (H). Aortic section from sham-infected mice devoid of infiltrating CD3+ T cells. Black arrow heads indicate atherosclerotic plaque. Red arrows indicate infiltrated CD3+ T cells. L—artery lumen, I—intimal layer, M—medial layer, A—adventitial layer. * p < 0.05.
Mentions: In order to determine the extent of polymicrobial infection-induced atherosclerotic plaque development, atherosclerotic plaque was measured in sections cut from the aortic root at the level of the valves to the abdominal aorta in infected and sham-infected mice (n = 6, both groups). Minimal plaque was detected in the thoracic and abdominal aorta as has been previously reported, however, plaque was detected in the aortic root and ascending aorta and plaque growth was compared for polymicrobial and non-infected animals at 12 and 24 weeks follow up. Plaque areas as well as intimal and medial thickness were measured, and the intimal thickness / medial thickness ratios were calculated for 12 and 24 week-infected mice. Mice at 12 weeks of infection had larger plaque areas than sham-infected mice, but this did not achieve statistical significance (Fig 5A). In contrast, at 24 weeks infected mice developed significantly increased plaque area (p < 0.05) on comparison to sham-infected mice at 24 weeks as well as when compared to 12 week-infected mice. By 24 weeks of infection, intimal / medial layer thickness ratios also demonstrated a trend toward increased plaque thickness in infected mice when compared to sham-infected mice which was not significant (p = 0.1339) Fig 5B and 5D–5E). Twenty four-weeks-infected mice had significantly (p = 0.0003) increased CD3+ T cell counts per high power field (100X HPF) in the intimal layer (Fig 5C and 5F–5G) when compared to the sham-infected mice (Fig 5H).

Bottom Line: Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis.Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES.In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.

ABSTRACT
Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Show MeSH
Related in: MedlinePlus