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Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease.

ABSTRACT: Treponema denticola, a periopathogen, evades complement-mediated killing by binding the negative complement regulatory protein factor H (FH) to its surface via the FhbB protein. Paradoxically, bound FH is cleaved by T. denticola's dentilisin protease, a process hypothesized to trigger localized dysregulation of complement activation in periodontal pockets. The ability of other oral treponemes to evade complement-mediated killing and bind and cleave FH has not been assessed. In this report, we demonstrate that representative isolates of Treponema socranskii, Treponema medium, Treponema pectinovorum and Treponema maltophilum are also serum resistant, whereas Treponema vincentii and Treponema amylovorum are serum sensitive. Although T. denticola's ability to evade complement-mediated killing is strictly dependent on FH binding, other serum-resistant treponemal species lack FhbB and do not bind FH, indicating an FH-independent mechanism of complement evasion. To assess the influence of FhbB sequence variation on FH binding and cleavage by T. denticola, fhbB sequences were determined for 30 isolates. Three distinct phyletic types were identified. All T. denticola strains bound FH and were serum resistant, but differences in binding kinetics, dentilisin activity and FH cleavage ability were observed. Based on these analyses, we hypothesize that the composition of the T. denticola population is a determining factor that influences the progression and severity of periodontal disease.

SUBMITTER: Miller DP

PROVIDER: S-EPMC4165728 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease.

Miller D P DP McDowell J V JV Bell J K JK Goetting-Minesky M P MP Fenno J C JC Marconi R T RT

Molecular oral microbiology 20140603 5

Treponema denticola, a periopathogen, evades complement-mediated killing by binding the negative complement regulatory protein factor H (FH) to its surface via the FhbB protein. Paradoxically, bound FH is cleaved by T. denticola's dentilisin protease, a process hypothesized to trigger localized dysregulation of complement activation in periodontal pockets. The ability of other oral treponemes to evade complement-mediated killing and bind and cleave FH has not been assessed. In this report, we de ...[more]

PMID: 24815960

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Project description:BackgroundPeriodontal diseases, such as periodontitis, are chronic inflammatory infections affecting the gingivae (gums), underlying connective tissues and bone that support the teeth. Oral treponemes (genus Treponema) are widely-considered to play important roles in periodontal disease etiology and pathogenesis; however, precise relationships remain to be fully established.MethodsA 16S rRNA clone library-based approach was used to comprehensively characterize and compare the diversity of treponeme taxa present in subgingival plaque sampled from periodontitis patients (n = 10) versus periodontitis-free controls (n = 10). 16S rRNA gene sequences were assigned to operational taxonomic units (OTUs) using a 99% identity cut-off A variety of taxonomy (OTU) and phylogeny-based statistical approaches were used to compare populations of treponeme OTUs present in both subject groups.ResultsA total of 615 plasmid clones containing ca. 1500 bp Treponema 16S rRNA gene sequences were obtained; 365 from periodontitis subjects, 250 from periodontitis-free controls. These were assigned to 110 treponeme OTUs. 93 OTUs were detected in the periodontitis subjects (mean 9.3 ± 5.2 OTUs per subject; range 9-26), and 43 OTUs were detected in controls (mean 4.3 ± 5.9 OTUs per subject; range 3-20). OTUs belonging to oral treponeme phylogroups 1-7 were detected in both subject sets. Phylogroup 1 treponemes had the highest levels of OTU richness (diversity) and clonal abundance within both subject groups. Levels of OTU richness and clonal abundance of phylogroup 2 treponemes were significantly higher in the periodontitis subjects (Mann Whitney U-test, p < 0.001). Both OTU-based and phylogeny-based analyses clearly indicated that there were significant differences in the composition of treponeme communities present in periodontitis versus control subjects. The detection frequency of five OTUs showed a statistically-significant correlation with disease status. The OTU (8P47) that corresponded to the type strain of Treponema denticola had the strongest association with periodontitis (p < 0.01).ConclusionsHigher levels of treponeme taxon richness and clonal abundance were associated with periodontitis. However, our results clearly indicated that subjects free from clinical symptoms of periodontal disease also contained highly diverse populations of treponeme bacteria within their subgingival microbiota. Our data supports the hypothesis that specific treponeme taxa are associated with periodontal disease.

Project description:The use of systemic antibiotics may influence the oral microbiota composition. Our aim was to investigate in this retrospective study whether the use of prescribed antibiotics associate with periodontal status, oral microbiota, and antibodies against the periodontal pathogens. The Social Insurance Institution of Finland Data provided the data on the use of systemic antibiotics by record linkage to purchased medications and entitled reimbursements up to 1 year before the oral examination and sampling. Six different classes of antibiotics were considered. The Parogene cohort included 505 subjects undergoing coronary angiography with the mean (SD) age of 63.4 (9.2) years and 65% of males. Subgingival plaque samples were analysed using the checkerboard DNA-DNA hybridisation. Serum and saliva antibody levels to periodontal pathogens were analysed with immunoassays and lipopolysaccharide (LPS) activity with the LAL assay. Systemic antibiotics were prescribed for 261 (51.7%) patients during the preceding year. The mean number of prescriptions among them was 2.13 (range 1-12), and 29.4% of the prescriptions were cephalosporins, 25.7% penicillins, 14.3% quinolones, 12.7% macrolides or lincomycin, 12.0% tetracycline, and 5.8% trimethoprim or sulphonamides. In linear regression models adjusted for age, sex, current smoking, and diabetes, number of antibiotic courses associated significantly with low periodontal inflammation burden index (PIBI, p < 0.001), bleeding on probing (BOP, p = 0.006), and alveolar bone loss (ABL, p = 0.042). Cephalosporins associated with all the parameters. The phyla mainly affected by the antibiotics were Bacteroidetes and Spirochaetes. Their levels were inversely associated with the number of prescriptions (p = 0.010 and p < 0.001) and directly associated with the time since the last prescription (p = 0.019 and p < 0.001). Significant inverse associations were observed between the number of prescriptions and saliva concentrations of Prevotella intermedia, Tannerella forsythia, and Treponema denticola and subgingival bacterial amounts of Porphyromonas gingivalis, P. intermedia, T. forsythia, and T. denticola. Saliva or serum antibody levels did not present an association with the use of antibiotics. Both serum (p = 0.031) and saliva (p = 0.032) LPS activity was lower in patients having any antibiotic course less than 1 month before sampling. Systemic antibiotics have effects on periodontal inflammation and oral microbiota composition, whereas the effects on host immune responses against the periodontal biomarker species seem unchanged.

Project description:Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3, and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined "supercontrols," as a reference group. "Supercontrols" are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6-9.9] years) and 83% lacked FHR1 (n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion (n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions (n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon (n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency ("supercontrols"). Rare likely pathogenetic variants in CFH, THBD, and C3 were found in 24% of cases (n = 6) compared to 2.1% of the "supercontrols" (P-value = 0.005). We also found that the CFH H3 and the CD46 GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies.

Project description:The estimation of oral microbiome (OM) taxonomic composition in periodontally healthy individuals can often be biased because the clinically periodontally healthy subjects for evaluation can already experience dysbiosis. Usually, they are included just based on the absence of clinical signs of periodontitis. Additionally, the age of subjects is used to be higher to correspond well with tested groups of patients with chronic periodontitis, a disorder typically associated with aging. However, the dysbiosis of the OM precedes the clinical signs of the disease by many months or even years. The absence of periodontal pockets thus does not necessarily mean also good periodontal health and the obtained image of "healthy OM" can be distorted.To overcome this bias, we taxonomically characterized the OM in almost a hundred young students of dentistry with precise oral hygiene and no signs of periodontal disease. We compared the results with the OM composition of older periodontally healthy individuals and also a group of patients with severe periodontitis (aggressive periodontitis according to former classification system). The clustering analysis revealed not only two compact clearly separated clusters corresponding to each state of health, but also a group of samples forming an overlap between both well-pronounced states. Additionally, in the cluster of periodontally healthy samples, few outliers with atypical OM and two major stomatotypes could be distinguished, differing in the prevalence and relative abundance of two main bacterial genera: Streptococcus and Veillonella. We hypothesize that the two stomatotypes could represent the microbial succession from periodontal health to starting dysbiosis. The old and young periodontally healthy subjects do not cluster separately but a trend of the OM in older subjects to periodontitis is visible. Several bacterial genera were identified to be typically more abundant in older periodontally healthy subjects.

Dataset Information

Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease.

Publications

Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease.

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