Association of β-defensin-1 gene polymorphisms with Pseudomonas aeruginosa airway colonization in cystic fibrosis

Tesse, Riccardina; Cardinale, Fabio; Santostasi, Teresa; Polizzi, Angela; Manca, Antonio; Mappa, Luigi; Iacoviello, Gaia; Robertis, Francesca De; Logrillo, Vito Paolo; Armenio, Lucio

doi:10.1038/sj.gene.6364440

Cited by 44 publications

(46 citation statements)

References 27 publications

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“…In the past, these promoter SNPs were analyzed in association studies on Crohn's disease (positive association with rs11362 and rs1800972 13 ), airway colonization in cystic fibrosis (positive association of rs11362 and rs1799946), 25 HIV infection (associations of rs1799946, 26 rs11362 27 and rs1800972 28 ) and chronic obstructive pulmonary disease (no association). 29 However, these studies were characterized by small sample sizes and studies did not replicate the observed associations, except for associations with HIV, which were identified in different, albeit small populations of mixed ethnicity.…”

Section: Defb1 Disease Associationmentioning

confidence: 99%

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

Schäefer¹,

Richter²,

Nothnagel³

et al. 2009

Genes Immun

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Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1. Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1, we investigated the associations of the selected variants in a large population (N ¼ 1337 cases and 2887 ethnically matched controls). The 3 0 untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P ¼ 0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11-1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio ¼ 2.2 (95% confidence interval: 1.16-4.35), P ¼ 0.02), and aggressive periodontitis (odds ratio ¼ 1.3 (95% confidence interval 1.04-1.68), P ¼ 0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031.

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Section: Defb1 Disease Associationmentioning

confidence: 99%

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

Schäefer¹,

Richter²,

Nothnagel³

et al. 2009

Genes Immun

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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).…”

mentioning

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.

176

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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“…Furthermore, three single nucleotide polymorphisms (SNPs) in the 5=-untranslated region of Defb1, namely, G-20A, C-44G, and G-52A, have been correlated with host susceptibility toward, e.g., Pseudomonas aeruginosa in cystic fibrosis patients (14), HIV infection (15, 16), Crohn's disease (17), sepsis (18), and asthma (19). The role of these SNPs is not fully understood, but it is hypothesized that they influence peptide production or function (14,20). It has not been investigated whether these SNPs have a correlation with UTI.…”

mentioning

confidence: 99%

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

Nielsen

Dynesen²,

Larsen³

et al. 2014

Infect Immun

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; Haslev Laegecenter, Haslev, Denmark c ; Laegehuset Ellemarksvej, Køge, Denmark d Cathelicidin (LL-37) and human ␤-defensin 1 (hBD-1) are important components of the innate defense in the urinary tract. The aim of this study was to characterize whether these peptides are important for developing uncomplicated Escherichia coli urinary tract infections (UTIs). This was investigated by comparing urinary peptide levels of UTI patients during and after infection to those of controls, as well as characterizing the fecal flora of participants with respect to susceptibility to LL-37 and in vivo virulence. Forty-seven UTI patients and 50 controls who had never had a UTI were included. Participants were otherwise healthy, premenopausal, adult women. LL-37 MIC levels were compared for fecal E. coli clones from patients and controls and were also compared based on phylotypes (A, B1, B2, and D). In vivo virulence was investigated in the murine UTI model by use of selected fecal isolates from patients and controls. On average, UTI patients had significantly more LL-37 in urine during infection than postinfection, and patient LL-37 levels postinfection were significantly lower than those of controls. hBD-1 showed similar urine levels for UTI patients and controls. Fecal E. coli isolates from controls had higher LL-37 susceptibility than fecal and UTI E. coli isolates from UTI patients. In vivo studies showed a high level of virulence of fecal E. coli isolates from both patients and controls and showed no difference in virulence correlated with the LL-37 MIC level. The results indicate that the concentration of LL-37 in the urinary tract and low susceptibility to LL-37 may increase the likelihood of UTI in a complex interplay between host and pathogen attributes.

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Association of β-defensin-1 gene polymorphisms with Pseudomonas aeruginosa airway colonization in cystic fibrosis

Cited by 44 publications

References 27 publications

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

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

Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections

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