Impaired β-Defensin Expression in Human Skin Links DEFB1 Promoter Polymorphisms With Persistent Staphylococcus aureus Nasal Carriage

Nurjadi, Dennis; Herrmann, Eva; Hinderberger, Isabel; Zanger, Philipp

doi:10.1093/infdis/jis735

Cited by 61 publications

(59 citation statements)

References 37 publications

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“…When consulting The National Center for Biotechnology Information bibliographic database, several entries, in part those dealing with caries, have been detected in the last 5 years reporting an association of functional findings concerning DEFB1 rs11362 SNP in the context of different pathologies such as chronic tonsillitis [Arslan et al, 2015], diabetes [Németh et al, 2014], HIV infection [Estrada-Aguirre et al, 2014], Crohn disease [Jung et al, 2012], Staphylococcus aureus infection [Fode et al, 2012;Nurjadi et al, 2013], contact lens keratitis [Carnt et al, 2012], atopic dermatitis [Segat et al, 2010], and in another oral pathological condition such as periodontitis [Ikuta et al, 2015]. So DEFB1 rs11362 SNP seems to have a potential impact on impairing hBD1 production, consequently leading to an augmented risk of infection from different pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…β-Defensin production has been theorized as being under genetic control, with the involvement of copy number variations in DEFB4 , DEFB103 , and DEFB104 genes coding for hBD2 [Jaradat et al, 2013] as well as hBD3 and hBD4, reviewed in Cantsilieris and White [2013], or regulatory 5 ′ -untranslated region (UTR) polymorphisms in the DEFB1 gene encoding hBD1 [Sun et al, 2006;Milanese et al, 2007;Kalus et al, 2009;Nurjadi et al, 2013].…”

mentioning

confidence: 99%

“…So, considering the important role hypothesized for the constitutively expressed hBD1 antimicrobial peptide in the predisposition to develop caries, as well as the genetic studies reporting association or lack of association between DEFB1 variants and susceptibility to caries experience in different ethnic groups, needing a replica, we analysed 5 DEFB1 polymorphisms, namely 3 functional single-nucleotide polymorphisms (SNPs) [Sun et al, 2006;Milanese et al, 2007;Kalus et al, 2009;Nurjadi et al, 2013] at 5 ′ -UTR, -52G>A (rs1799946), -44C>G (rs1800972), and -20G>A (rs11362), and 2 SNPs at 3 ′ -UTR, c * 5G>A (rs1047031) and c * 87A>G (rs1800971), the latter located in possible miRNA binding sites and potential modifiers of hBD1 protein expression [PradoMontes et al, 2009], looking for possible associations with the risk to develop caries in isolated populations from north-eastern Italy.…”

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Caries and Innate Immunity: DEFB1 Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy

et al. 2016

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Background: The DEFB1 gene, encoding for the constitutively expressed human β-defensin 1 (hBD1) antimicrobial peptide is a potential candidate when studying genetic susceptibility to caries. DEFB1 genetic variations have been reported as contributing to hBD1 production impairment, leading to a greater susceptibility to be infected by oral pathogens, also leading to periodontitis. Methods: We analysed 5 DEFB1 polymorphisms, namely 3 functional single-nucleotide polymorphisms (SNPs) at the 5′-untranslated region (UTR), -52G>A (rs1799946), -44C>G (rs1800972), and -20G>A (rs11362), 2 SNPs at the 3′-UTR, c*5G>A (rs1047031) and c*87A>G (rs1800971) SNP located in potential miRNA binding sites, looking for possible correlations with the risk to develop caries in 654 adult subjects from isolated populations of north-eastern Italy. Dental caries prevalence was evaluated with the DMFT (decayed, missing, filled teeth) index, calculated after an accurate oral examination. DEFB1 SNP genotyping was performed with an Illumina 370k high-density SNP array. Results: Two DEFB1 SNPs were significantly associated with the DMFT index: the strongest association emerged from rs11362 SNP (p = 0.008). In particular G/G homozygous individuals showed a higher DMFT index compared to both G/A heterozygous and A/A homozygous individuals; rs1799946 SNP was also significantly associated with DMFT (p = 0.030), and individuals homozygous for the T allele had a higher DMFT value compared to heterozygous C/T and homozygous C/C individuals. Conclusions: Our study replicated, on a larger number of individuals, previous findings showing the association between two 5′-UTR SNPs in the DEFB1 gene and DMFT, suggesting that these polymorphisms could be considered as potential markers for assessing the risk to develop caries.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Caries and Innate Immunity: DEFB1 Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy

et al. 2016

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“…Some suggested that polymorphisms in the defensin gene cluster modulate the phenotype of cystic fibrosis (CF) airway disease, including an association with chronic P. aeruginosa infection (25)(26)(27). In addition, a genetic variant in the promoter region of a defensin gene cluster was associated with reduced hBD-1 and hBD-3 transcript levels and a higher risk of persistent S. aureus nasal colonization in a cohort of healthy individuals (28). However, two reports did not identify an association, perhaps because the populations studied had different genetic backgrounds (29,30).…”

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confidence: 99%

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Alaiwa¹,

Reznikov²,

Gansemer³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

172

162

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The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.

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“…Multiple studies have determined that defensin gene polymorphisms, both in sequence and in gene copy numbers, do not seem to be involved in S. aureus carriage predisposition (15,16). In contrast, polymorphisms in the DEFB1 gene promoter region, a regulator of hBD-1 and hBD-3, were associated with lower hBD-3 expression and persistent S. aureus nasal colonization (17).…”

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confidence: 99%

Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

et al. 2016

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g Approximately 20% of the population is persistently colonized by Staphylococcus aureus in the nares. Th17-like immune responses mediated by the interleukin-17 (IL-17) family of cytokines and neutrophils are becoming recognized as relevant host defense mechanisms for resolution of S. aureus mucocutaneous infections. Since antimicrobial peptides are regulated by the IL-17 cytokines, we sought to determine the role of IL-17 cytokines in production of antimicrobial peptides in a murine model of S. aureus nasal carriage. We discovered that nasal tissue supernatants have antistaphylococcal activity, and mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus nasal colonization. IL-17A was found to be sufficient for nasal mBD-3 production ex vivo and was required for CRAMP, mBD-3, and mBD-14 expression in response to S. aureus colonization in vivo. These data were confirmed in a clinical study of nasal secretions in which elevated levels of the human forms of these antimicrobial peptides were found in nasal secretions from healthy human subjects when they were colonized with S. aureus but not in secretions from noncolonized subjects. Together, these data provide evidence for the importance of IL-17A regulation of antimicrobial peptides and IL-17F in the clearance of S. aureus nasal carriage.

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Impaired β-Defensin Expression in Human Skin Links DEFB1 Promoter Polymorphisms With Persistent Staphylococcus aureus Nasal Carriage

Abstract: DEFB1 polymorphisms may promote persistent S. aureus colonization by altering β-defensin expression in keratinocytes of human skin.

Cited by 61 publications

References 37 publications

Caries and Innate Immunity: <b><i>DEFB1</i></b> Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy

Caries and Innate Immunity: <b><i>DEFB1</i></b> Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy

pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37

Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization

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