Association of Interacting Genes in the Toll-Like Receptor Signaling Pathway and the Antibody Response to Pertussis Vaccination

BACKGROUND: Activation of the Toll-like receptor (TLR) signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs) in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV) pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT)-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894) in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell membrane of antigen-presenting cells, B cells, or both. Fine tuning of interacting proteins in the TLR pathway appears important for the induction of an optimal vaccine response

Immune Phenotype and Function of Natural Killer and T Cells in Chronic Hepatitis C Patients Who Received a Single Dose of Anti-MicroRNA-122, RG-101

MicroRNA‐122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG‐101, an N‐acetylgalactosamine‐conjugated anti‐microRNA‐122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG‐101 therapy on antiviral immunity. Thirty‐two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG‐101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG‐101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon‐γ‐induced protein 10 (IP‐10) levels declined significantly upon dosing with RG‐101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon‐γ production decreased after RG‐101 dosing. Functional HCV‐specific interferon‐γ T‐cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post–RG‐101 injection. No increase in the magnitude of HCV‐specific T‐cell responses was observed at later time points, including 3 patients who were HCV RNA–negative 76 weeks postdosing. Conclusion: Dosing with RG‐101 is associated with a restoration of NK‐cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV‐specific T‐cell responses did not increase following RG‐101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG‐101 therapy

Gut microbiota composition and development of atopic manifestations in infancy: the KOALA birth cohort study

BACKGROUND AND AIMS: Perturbations in intestinal microbiota composition due to lifestyle changes may be involved in the development of atopic diseases. We examined gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation. METHODS: The faeces of 957 infants aged 1 month and participating in the KOALA Birth Cohort Study were analysed using quantitative real-time PCR. Information on atopic symptoms (eczema, wheeze) and potential confounders was acquired through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits when the infant was 2 years old. During these home visits a clinical diagnosis of atopic dermatitis was made according to the UK-Working Party criteria. RESULTS: The presence of Escherichia coli was associated with a higher risk of developing eczema (OR(adj) = 1.87; 95% CI 1.15 to 3.04), this risk being increased with increasing numbers of E coli (p(for trend) = 0.016). Infants colonised with Clostridium difficile were at higher risk of developing eczema (OR(adj) = 1.40; 95% CI 1.02 to 1.91), recurrent wheeze (OR(adj) = 1.75; 95% CI 1.09 to 2.80) and allergic sensitisation (OR(adj) = 1.54; 95% CI 1.02 to 2.31). Furthermore, the presence of C difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (OR(adj) = 1.73; 95% CI 1.08 to 2.78). CONCLUSION: This study demonstrates that differences in gut microbiota composition precede the development of atopy. Since E coli was only associated with eczema and C difficile was associated with all atopic outcomes, the underlying mechanisms explaining these association may be differen

Risk of infection and adverse outcomes among pregnant working women in selected occupational groups: A study in the Danish National Birth Cohort

<p>Abstract</p> <p>Background</p> <p>Exposure to infectious pathogens is a frequent occupational hazard for women who work with patients, children, animals or animal products. The purpose of the present study is to investigate if women working in occupations where exposure to infections agents is common have a high risk of infections and adverse pregnancy outcomes.</p> <p>Methods</p> <p>We used data from the Danish National Birth Cohort, a population-based cohort study and studied the risk of Infection and adverse outcomes in pregnant women working with patients, with children, with food products or with animals. The regression analysis were adjusted for the following covariates: maternal age, parity, history of miscarriage, socio-occupational status, pre-pregnancy body mass index, smoking habit, alcohol consumption.</p> <p>Results</p> <p>Pregnant women who worked with patients or children or food products had an excess risk of sick leave during pregnancy for more than three days. Most of negative reproductive outcomes were not increased in these occupations but the prevalence of congenital anomalies (CAs) was slightly higher in children of women who worked with patients. The prevalence of small for gestational age infants was higher among women who worked with food products. There was no association between occupation infections during pregnancy and the risk of reproductive failures in the exposed groups. However, the prevalence of CAs was slightly higher among children of women who suffered some infection during pregnancy but the numbers were small.</p> <p>Conclusion</p> <p>Despite preventive strategies, working in specific jobs during pregnancy may impose a higher risk of infections, and working in some of these occupations may impose a slightly higher risk of CAs in their offspring. Most other reproductive failures were not increased in these occupations.</p

Schistosoma haematobium Treatment in 1–5 Year Old Children: Safety and Efficacy of the Antihelminthic Drug Praziquantel

Urogenital schistosomiasis is an important, but neglected, infectious disease affecting over 100 million people, mainly in Africa. Children carry the heaviest burden of infection with children as young as 1 year old showing signs of infection. Children aged 5 years and below are currently excluded from schistosome control programmes for several reasons, including operational difficulties associated with accessing preschool children, misconceptions about their level of exposure to infective water and lack of safety data on the drug of choice for schistosome control, praziquantel, in children aged 5 years and below. This study was one of a small number of studies recently funded by the World Health Organization to investigate the need for praziquantel treatment in preschool children (aged 1–5 years) and to subsequently assess the safety and efficacy of the drug praziquantel in this age group. This study confirmed that preschool children carry significant levels of schistosome infection, exceeding those carried by their parents/guardians, highlighting the urgent need for their immediate inclusion in schistosome control programmes. The study also showed that praziquantel treatment is as safe and efficacious in children aged 1–5 years as it is in older children aged 6–10 years who are currently the target for mass drug administration

The discourse dynamics approach to metaphor and metaphor-led discourse analysis

The use of metaphor as a tool to uncover people's ideas, attitudes, and values through analysis of discourse is demonstrated and illustrated with data collected in a social science research project. A 'discourse dynamics' approach to metaphor situated within a complexity/dynamic systems perspective is developed. This approach is turned into a method of 'metaphor-led discourse analysis' which is described in detail, using a focus group discussion to illustrate the procedure: transcription, metaphor identification, coding metaphors and using software, and finding patterns of metaphor use from coded data. The reasoning that justifies decisions at each stage of the procedure is made explicit so that the trustworthiness of the method can be maximized. The method of metaphor-led discourse analysis has been developed through a series of empirical projects to be accessible and relevant to social science researchers as well as to metaphor scholars

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age