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  • 1
    Language: English
    In: Clinical Infectious Diseases, Vol.52(4), pp.475-480
    Description: Comparing the frequency of TLR9 polymorphisms in bacterial meningitis survivors with healthy controls we found a protective mutant allele. We showed that carriage of this mutant strongly modifies the immunoinhibitory potential of Neisseria meningitidis leading to a decreased susceptibility to meningitis. Background. Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. Methods . We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. Results . Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4–.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0–1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). Conclusions . We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA.
    Keywords: Medicine;
    ISSN: 1058-4838
    E-ISSN: 15376591
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e35837
    Description: Genetic variation in innate immune response genes contributes to inter-individual differences in disease manifestation and degree of complications upon infection. We recently described an association of single nucleotide polymorphisms (SNPs) in TLR9 with susceptibility to meningococcal meningitis (MM). In this study, we investigate the association of SNPs in multiple pathogen recognition and immune response genes with clinical features that determine severity and outcome (especially hearing loss) of childhood MM and pneumococcal meningitis (PM). Eleven SNPs in seven genes ( TLR2 , TLR4, TLR9 , NOD1 , NOD2 , CASP1, and TRAIL ) were genotyped in 393 survivors of childhood bacterial meningitis (BM) (327 MM patients and 66 PM patients). Genotype distributions of single SNPs and combination of SNPs were compared between thirteen clinical characteristics associated with severity of BM. After correction for multiple testing, TLR4 +896 mutant alleles were highly associated with post-meningitis hearing loss, especially MM ( p  = 0.001, OR 4.0 for BM, p  = 0.0004, OR 6.2 for MM). In a multigene analysis, combined carriership of the TLR2 +2477 wild type (WT) with TLR4 +896 mutant alleles increases the risk of hearing loss ( p 〈0.0001, OR 5.7 in BM and p  = 0.0001, OR 7.6 in MM). Carriage of one or both mutant alleles in TLR4 +896 and TLR9 -1237 increases the risk for hearing loss ( p  = 0.0006, OR 4.1 in BM). SNPs in immune response genes contribute to differences in clinical severity and outcome of BM. The TLR system seems to play an important role in the immune response to BM and subsequent neuronal damage as well as in cochlear inflammation. Genetic markers may be used for identification of high-risk patients by creating prediction rules for post-meningitis hearing loss and other sequelae, and provide more insight in the complex immune response in the CNS possibly resulting in new therapeutic interventions.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Immunology ; Neurological Disorders ; Biochemistry ; Infectious Diseases ; Computational Biology ; Evolutionary Biology ; Pediatrics And Child Health
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: 2014, Vol.9(4), p.e93939
    Description: The immune system eliminates Chlamydia trachomatis infection through inflammation. However, uncontrolled inflammation can enhance pathology. In mice, TNF-related apoptosis-inducing ligand receptor (TRAIL-R), known for its effects on apoptosis, also regulates inflammation. In humans, the four homologues of TRAIL-R had never been investigated for effects on inflammation. Here, we examined whether TRAIL-R regulates inflammation during chlamydial infection. We examined TRAIL-R1 single nucleotide polymorphisms (SNPs) in an Ecuadorian cohort with and without C. trachomatis infections. There was a highly significant association for the TRAIL+626 homozygous mutant GG for infection vs no infection in this population. To confirm the results observed in the human population, primary lung fibroblasts and bone marrow-derived macrophages (BMDMs) were isolated from wildtype (WT) and TRAIL-R-deficient mice, and TRAIL-R1 levels in human cervical epithelial cells were depleted by RNA interference. Infection of BMDMs and primary lung fibroblasts with C. trachomatis strain L 2 , or the murine pathogen C. muridarum , led to higher levels of MIP2 mRNA expression or IL-1β secretion from TRAIL-R-deficient cells than WT cells. Similarly, depletion of TRAIL-R1 expression in human epithelial cells resulted in a higher level of IL-8 mRNA expression and protein secretion during C. trachomatis infection. We conclude that human TRAIL-R1 SNPs and murine TRAIL-R modulate the innate immune response against chlamydial infection. This is the first evidence that human TRAIL-R1 is a negative regulator of inflammation and plays a role in modulating Chlamydia pathogenesis.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Journal of Infectious Diseases, 2016, Vol.214(3), pp.489-495
    Keywords: Haemophilus Ducreyi ; Chancroid ; Skin Ulcers ; Immunogenetics ; Humans ; Innate Immunity
    ISSN: 0022-1899
    ISSN: 1537-6613
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  • 5
    In: The Journal of Infectious Diseases, 2016, Vol. 214(3), pp.489-495
    Description: Background.  In humans inoculated with Haemophilus ducreyi , there are host effects on the possible clinical outcomes—pustule formation versus spontaneous resolution of infection. However, the immunogenetic factors that influence these outcomes are unknown. Here we examined the role of 14 single-nucleotide polymorphisms (SNPs) in 7 selected pathogen-recognition pathways and cytokine genes on the gradated outcomes of experimental infection. Methods.  DNAs from 105 volunteers infected with H. ducreyi at 3 sites were genotyped for SNPs, using real-time polymerase chain reaction. The participants were classified into 2 cohorts, by race, and into 4 groups, based on whether they formed 0, 1, 2, or 3 pustules. χ 2 tests for trend and logistic regression analyses were performed on the data. Results.  In European Americans, the most significant findings were a protective association of the TLR9 +2848 GG genotype and a risk-enhancing association of the TLR9 TA haplotype with pustule formation; logistic regression showed a trend toward protection for the TLR9 +2848 GG genotype. In African Americans, logistic regression showed a protective effect for the IL10 – 2849 AA genotype and a risk-enhancing effect for the IL10 AAC haplotype. Conclusions.  Variations in TLR9 and IL10 are associated with the outcome of H. ducreyi infection.
    Keywords: 〈Kwd〉〈Italic Toggle="Yes"〉Haemophilus Ducreyi〈/Italic〉〈/Kwd〉 ; Chancroid ; Skin Ulcers ; Immunogenetics ; Humans ; Innate Immunity
    ISSN: 0022-1899
    E-ISSN: 1537-6613
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  • 6
    In: JAMA, The Journal of the American Medical Association, April 4, 2001, Vol.285(13), p.1703
    Keywords: Chlamydia Infections -- Health Aspects ; Cervical Cancer -- Risk Factors ; Squamous Cell Carcinoma -- Risk Factors
    ISSN: 0098-7484
    E-ISSN: 15383598
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  • 7
    Language: English
    In: The Journal of infectious diseases, September 2013, Vol.208(6), pp.969-77
    Description: Previous studies identified specific Chlamydia trachomatis strains circulating among men who have sex with men (MSM). This study investigates whether distinct C. trachomatis strains circulate among subpopulations within the MSM community. Participants were recruited at the sexually transmitted infection clinic of the Public Health Service of Amsterdam from 2008 to 2009. C. trachomatis samples were typed using multilocus sequence typing. Epidemiological and clinical data were derived from questionnaires and patient records. Typing of 277 samples from 260 MSM identified distinct C. trachomatis strains circulating concurrently over time. Men with lymphogranuloma venereum (LGV)-inducing strains were more likely to be infected with human immunodeficiency virus, more often had a history of STI, and had a higher frequency of risky sexual behavior. No such associations were found for non-LGV-inducing strains. MSM infected with heterosexual-associated strains were often younger (P = .04) and more often reported sex with women (P = .03), compared with men infected with MSM-associated strains. With the exception of LGV-inducing strains, no evidence was found that different C. trachomatis strains circulated in distinct subpopulations of MSM. This indicates that no separate transmission networks for C. trachomatis among MSM existed. However, younger MSM and bisexuals were more often infected with heterosexual-associated C. trachomatis strains.
    Keywords: Chlamydia Trachomatis ; HIV ; Cluster Analysis ; Epidemiology ; High-Resolution Genotyping ; Lymphogranuloma Venereum ; Men Who Have Sex With Men ; Homosexuality, Male ; Multilocus Sequence Typing ; Chlamydia Trachomatis -- Classification ; DNA, Bacterial -- Isolation & Purification ; Lymphogranuloma Venereum -- Transmission
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 8
    Language: English
    In: Personalized Medicine, 2014, Vol.11(1), pp.41-62
    Description: Background: Recently, there has been a substantial increase in relevant genome-based technologies into market. Compared with its utilization in healthcare systems, we notice a huge gap. In order to address this bottleneck, we previously developed the Learning-Adapting-Leveling (LAL) model. Aim: In this article, we aim to demonstrate the overarching reach of the model for translation to market and implementation into healthcare systems moving towards personalized healthcare. Methods: We use qualitative logical reasoning with the LAL model as a reference. Results: We found that technology transfer, health needs assessment, health technology assessment and health impact assessment are justified for their inclusion. In addition, the public health wheel is justified as a good reference frame along with value of information. Conclusion: We conclude that as the LAL model covers all dimensions and tools for translation and implementation in a defined method; it can therefore be considered as the overarching framework for translation and implementation into healthcare.
    Keywords: Acce/Egapp ; Health Impact Assessment ; Health Needs Assessment ; Health Technology Assessment ; Learning-Adapting-Leveling Model ; Personalized Healthcare ; Public Health Genomics ; Public Health Wheel ; Technology Transfer ; Translational Research
    ISSN: 1741-0541
    E-ISSN: 1744828X
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  • 9
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e34108
    Description: Current test-of-cure practice in patients with Chlamydia trachomatis (Ct) infection is to confirm cure with a single test taken at least 3 weeks after treatment. Effectiveness of single-time-point testing however lacks a scientific evidence basis and the high sensitivity of laboratory assays nowadays in use for this purpose may compromise the clinical significance of their results. Prospectively following 59 treated Ct infections, administering care as usual, the presence of Ct plasmid DNA and rRNA was systematically assessed by multiple time-sequential measurements, i.e. on 18 samples taken per patient during 8 weeks following treatment with a single dose of 1000 mg Azythromycin. A high proportion (42%) of Ct infections tested positive on at least one of the samples taken after 3 weeks. Patients' test results showed substantial inter-individual and intra-individual variation over time and by type of NAAT used. We demonstrated frequent intermittent positive patterns in Ct test results over time, and strongly argue against current test-of-cure practice.
    Keywords: Research Article ; Medicine ; Public Health And Epidemiology ; Infectious Diseases
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: PLoS ONE, 2012, Vol.7(2), p.e32122
    Description: In general, point-of-care (POC) tests for Chlamydia trachomatis (Ct) show disappointing test performance, especially disappointing sensitivity results. However, one study sponsored by the manufacturer (Diagnostics for the Real World) reported over 80% sensitivity with their Chlamydia Rapid Test (CRT). We evaluated the performance of this CRT in a non–manufacturer-sponsored trial. ; Between July 2009 and February 2010, we included samples from 912 women in both high- and low-risk clinics for sexually transmitted infections (STIs) in Paramaribo, Suriname. Sensitivity, specificity, positive- and negative predictive values (PPV and NPV) for CRT compared to NAAT (Aptima, Gen-Probe) were determined. Quantitative Ct load and human cell load were determined in all CRT and/or NAAT positive samples. ; CRT compared to NAAT showed a sensitivity and specificity of 41.2% (95% CI, 31.9%–50.9%) and 96.4% (95% CI, 95.0%–97.5%), respectively. PPV and NPV were 59.2% (95% CI, 47.5%–70.1%) and 92.9% (95% CI, 91.0%–94.5%), respectively. Quantitative Ct bacterial load was 73 times higher in NAAT-positive/CRT-positive samples compared to NAAT-positive/CRT-negative samples (p〈0.001). Human cell load did not differ between true-positive and false-negative CRT results (p = 0.835). Sensitivity of CRT in samples with low Ct load was 12.5% (95% CI, 5.2%–24.2%) and in samples with high Ct load 73.5% (95% CI, 59.9%–84.4%). ; The sensitivity of CRT for detecting urogenital Ct in this non–manufacturer-sponsored study did not meet the expectations as described previously. The CRT missed samples with a low Ct load. Improved POC are needed as meaningful diagnostic to reduce the disease burden of Ct.
    Keywords: Research Article ; Biology ; Medicine ; Infectious Diseases
    E-ISSN: 1932-6203
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