Oral Streptococci Exhibit Diverse Susceptibility to Human �-Defensin-2: Antimicrobial Effects of hBD-2 on Oral Streptococci

Nishimura, Eisaku; Eto, Akiko; Kato, Masaaki; Hashizume, Shuichi; Imai, Shoichi; Nisizawa, Tosiki; Hanada, Nobuhiro

doi:10.1007/s00284-003-4108-3

Cited by 54 publications

(53 citation statements)

References 12 publications

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“…In this age of antibiotic resistance, the idea of using natural antimicrobial peptides or their synthetic derivatives to combat bacterial and fungal infections is particularly appealing. The use of antimicrobial peptides as dental therapeutics to combat periodontal disease and caries has been posited, and a number of oral microbes have demonstrated sensitivity to these peptides in vitro (34,41,43,44,47,48). However, we have demonstrated that T. denticola and several other oral treponemes are not vulnerable to human ␤-defensins (9,10).…”

Section: Discussionmentioning

confidence: 75%

Mechanisms of Decreased Susceptibility to β-Defensins byTreponema denticola

Brissette¹,

Lukehart

2007

Infect Immun

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Treponema denticola, a periodontal pathogen, is relatively resistant to human beta-defensins, which are small cationic antimicrobial peptides produced by a number of cells, including the gingival epithelium. Using two independent methods, we previously demonstrated that T. denticola proteases are not responsible for decreased vulnerability to defensins. In this study, we confirmed that the major outer membrane protease, dentilisin, is not responsible for T. denticola insensitivity to defensins and examined several other possible mechanisms, including reduced binding to the bacterial surface and efflux pump activity. It has been suggested that some bacteria mask their surfaces with serum proteins. T. denticola grown in a serum-free medium did not exhibit increased susceptibility to human beta-defensin 2 and 3 (h␤D-2 and h␤D-3, respectively), suggesting that cloaking of the outer surface with host proteins is not involved in defensin resistance. Nonetheless, we demonstrated that T. denticola binds significantly less h␤D-2 and -3 than susceptible organisms bind, suggesting that the unusual outer membrane composition of T. denticola may discourage cationic peptide binding. Efflux pumps have been shown to mediate resistance to antibiotics and cationic peptides in other bacteria, and their role in T. denticola's relative resistance to ␤-defensins was investigated. Three inhibitors of bacterial ATP-binding cassette (ABC) efflux pumps had no effect on T. denticola's susceptibility to h␤D-2 or -3. In contrast, a proton motive force inhibitor, carbonyl cyanide 3-chlorophenylhydrazone, increased the susceptibility of T. denticola to killing by h␤D-3, demonstrating a potential role for efflux pumps (other than ABC pumps) in resistance to this peptide. Our data suggest that the combination of decreased defensin binding and efflux of any peptide which enters the cytoplasm may explain T. denticola's relative resistance to human beta-defensins.

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Section: Discussionmentioning

confidence: 75%

Mechanisms of Decreased Susceptibility to β-Defensins byTreponema denticola

Brissette¹,

Lukehart

2007

Infect Immun

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“…The defensins and cathelicidins have broad antimicrobial activity against gram-negative and gram-positive bacteria and Candida albicans and are effective in vitro against oral microorganisms such as Streptococcus mutans, Porphyromonas gingi-valis, and Actinobacillus actinomycetemcomitans (5,13,25,35). The cathelicidins and ␣-and ␤-defensins act synergistically with other antimicrobials (19,24).…”

mentioning

confidence: 99%

Salivary Antimicrobial Peptide Expression and Dental Caries Experience in Children

Tao¹,

Jurevic²,

Coulton³

et al. 2005

Antimicrob Agents Chemother

186

170

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Dental caries is a major worldwide oral disease problem in children. Although caries are known to be influenced by dietary factors, the disease results from a bacterial infection; thus, caries susceptibility may be affected by host factors such as salivary antimicrobial peptides. This study aimed to determine a possible correlation between caries prevalence in children and salivary concentrations of the antimicrobial peptides human beta-defensin-3 (hBD-3), the cathelicidin LL37, and the alpha-defensins HNP1-3 (a mixture of HNP1, 2, 3). Oral examinations were performed on 149 middle school children, and unstimulated whole saliva was collected for immunoassays of the three peptides and for assay of caries-causing bacteria in saliva. The median salivary levels of hBD-3, LL37, and HNP1-3 were in the microgram/ml range but were highly variable in the population. While levels of LL37 and hBD-3 did not correlate with caries experience, the median HNP1-3 levels were significantly higher in children with no caries than in children with caries. Children with high caries levels did not have high levels of salivary Streptococcus mutans, and the HNP1-3 level was not correlated with salivary S. mutans. By immunohistochemistry we localized HNP1-3 in submandibular salivary duct cells. HNPs are also released by neutrophils into the gingival crevicular fluid. Both sources may account for their presence in saliva. Low salivary levels of HNP1-3 may represent a biological factor that contributes to caries susceptibility. This observation could lead to new ways to screen for caries susceptibility and to new means of assessing the risk for this common oral problem.

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“…It is interesting that the recombinant lysine variant of LTF expressed in an insect vector also induced an upregulation of epithelial production of human beta defensin 2 (hBD-2) (11). hBD-2 has been shown to have significant antibacterial activity against S. mutans and S. sobrinus, two cariogenic microbes (29). Conversely, hBD-2 has been shown to have little to no effect on several Gramnegative periodontal pathogens (30).…”

Section: Discussionmentioning

confidence: 99%

A Lactotransferrin Single Nucleotide Polymorphism Demonstrates Biological Activity That Can Reduce Susceptibility to Caries

Fine

Toruner²,

Velliyagounder

et al. 2013

Infect Immun

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bStreptococcus mutans is prominently linked to dental caries. Saliva's influence on caries is incompletely understood. Our goal was to identify a salivary protein with anti-S. mutans activity, characterize its genotype, and determine genotypic variants associated with S. mutans activity and reduced caries. An S. mutans affinity column was used to isolate active moieties from saliva obtained from a subject with minimal caries. The bound and eluted protein was identified as lactotransferrin (LTF) by matrixassisted laser desorption ionization-time of flight (MALDI-TOF) analysis and confirmed by Western blotting with LTF antibody. A single nucleotide polymorphism (SNP) that produced a shift from arginine (R) to lysine (K) at amino acid position 47 in the LTF antimicrobial region (rs: 1126478) killed S. mutans in vitro. Saliva from a subject with moderate caries and with the LTF "wild-type" R form at position 47 had no such activity. A pilot genetic study (n ‫؍‬ 30) showed that KK subjects were more likely to have anti-S. mutans activity than RR subjects (P ‫؍‬ 0.001; relative risk ‫؍‬ 3.6; 95% confidence interval [95% CI] ‫؍‬ 1.5 to 11.13). Pretreatment of KK saliva with antibody to LTF reduced S. mutans killing in a dose-dependent manner (P ‫؍‬ 0.02). KK subjects were less likely to have caries (P ‫؍‬ 0.02). A synthetic 11-mer LTF/K peptide killed S. mutans and other caries-related bacteria, while the LTF/R peptide had no effect (P ‫؍‬ 0.01). Our results provide functional evidence that the LTF/K variant results in both anti-S. mutans activity and reduced decay. We suggest that the LTF/K variant can influence oral microbial ecology in general and caries-provoking microbes specifically.

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Oral Streptococci Exhibit Diverse Susceptibility to Human �-Defensin-2: Antimicrobial Effects of hBD-2 on Oral Streptococci

Cited by 54 publications

References 12 publications

Mechanisms of Decreased Susceptibility to β-Defensins byTreponema denticola

Mechanisms of Decreased Susceptibility to β-Defensins byTreponema denticola

Salivary Antimicrobial Peptide Expression and Dental Caries Experience in Children

A Lactotransferrin Single Nucleotide Polymorphism Demonstrates Biological Activity That Can Reduce Susceptibility to Caries

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