Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

Abstract: The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here, we report the molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for resistance to neutrophil killing. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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GENETIC VARIATION OF IL13 AS A RISK FACTOR OF REDUCED LUNG FUNCTION IN CHILDREN AND ADOLESCENTS: A CROSS-SECTIONAL POPULATION-BASED STUDY IN KOREA

Background: Previous investigations have suggested that genetic variations are associated with reduced lung function in early childhood. This study was conducted to evaluate the association between IL13 + 2044G -> A, the functionally relevant single nucleotide polymorphism (SNP) in the gene coding IL13, and lung function in early childhood. Patients and methods: A total of 1900 subjects aged 10-18 years living in Korea, were randomly recruited. Lung function test and methacholine bronchial provocation test were performed. Multiple regression analysis adjusting for sex, age, height, atopy, and history of passive smoking was done to evaluate effect of IL13 + 2044G -> A on lung function. Results: Mean (SD) forced expiratory volume in 1s (FEV1) was 2.66 L (+/- 0.60) in subjects with the AA or AG genotype (n = 982) and 2.75 L (+/- 0.57) in subjects with the GG genotype In = 918). IL13 + 2044G -> A showed a significant association with FEV1 [in the minor allele dominant model (GG vs. AG + AA), P A remained still significant in subgroup analysis according to the presence of AHR (P A in both groups (P A is significantly associated with a reduced lung function in Korean children and adolescents. (C) 2008 Elsevier Ltd. All rights reserved.X1114sciescopu

Allelic variants of CD40 and CD40L genes interact to promote antibiotic-induced cutaneous allergic reactions

P>Background The danger hypothesis provides a new perspective of the mechanisms underlying drug allergy. In this study, we evaluated associations between variations in the genes involved in danger signal pathways and antibiotic-induced cutaneous allergic reactions (AICARs). Methods Two hundred cases with urticaria, angio-oedema, maculopapular rash, and erythema multiforme caused by antibiotics were extracted from the database of the Adverse Drug Reaction Research Group in Korea. All cases were confirmed by an allergy specialist. Causative antibiotics included penicillin, cephalosporin, quinolone, and others (approximately 40 different types). Ten single nucleotide polymorphisms (SNPs) in seven genes (-318C > T, +49A > G, and +6230G > A in CTLA4, IVS+17T > C in CD28, -3479T > G and I170V in CD86, -1C > T in CD40, -3458A > G in CD40LG, -308G > A in TNF, and -31T > C in IL1B) were scored for cases and for healthy subjects without a history of AICARs. Results Our analysis failed to reveal differences in the distribution of the 10 SNPs between cases and controls. However, we could find a gene-gene interaction between -1C > T in CD40 and -3458A > G in CD40L using multifactor dimensionality reduction analysis. Subjects with minor alleles of both SNPs showed a significant risk for developing AICARs [P=0.017, odds ratio (OR) (95% confidence interval)=2.93 (1.20-7.97)]. Conclusion Our findings suggest that a genetic interaction between CD40 and CD40L favours the development of AICARs. Cite this as: Sae-H Kim, J-E Lee, Sang-H Kim, Y-K Jee, Y-K Kim, H-S Park, K-U Min, H-W Park and The Adverse Drug Reaction Research Group in Korea, Clinical & Experimental Allergy, 2009 (39) 1852-1856.X1178sciescopu

An image-based drug susceptibility assay targeting the placental sequestration of Plasmodium falciparum-infected erythrocytes.

Placental malaria is a significant cause of all malaria-related deaths globally for which no drugs have been developed to specifically disrupt its pathogenesis. To facilitate the discovery of antimalarial drugs targeting the cytoadherence process of Plasmodium-infected erythrocytes in the placenta microvasculature, we have developed an automated image-based assay for high-throughput screening for potent cytoadherence inhibitors in vitro. Parasitized erythrocytes were drug-treated for 24 h and then allowed to adhere on a monolayer of placental BeWo cells prior to red blood cell staining with glycophorin A antibodies. Upon image-acquisition, drug effects were quantified as the proportion of treated parasitized erythrocytes to BeWo cells compared to the binding of untreated iRBCs. We confirmed the reliability of this new assay by comparing the binding ratios of CSA- and CD36-panned parasites on the placental BeWo cells, and by quantifying the effects of chondroitin sulfate A, brefeldin A, and artemisinin on the binding. By simultaneously examining the drug effects on parasite viability, we could discriminate between cytoadherence-specific inhibitors and other schizonticidal compounds. Taken together, our data establish that the developed assay is highly suitable for drug studies targeting placental malaria, and will facilitate the discovery and rapid development of new therapies against malaria

Association between genetic variations in prostaglandin E-2 receptor subtype EP3 gene (Ptger3) and asthma in the Korean population

Background Recent investigations suggest that prostaglandin E-2 (PGE(2)) is important in the pathogenesis of not only aspirin-intolerant asthma but also asthma unrelated to aspirin intolerance. Objectives This study was conducted to evaluate the effects of variations in the gene coding PGE(2) receptor subtype EP1-4 (Ptger1-4) on the risk of asthma in the Korean population. Methods Nineteen single nucleotide polymorphisms (SNPs) were selected after re-sequencing Ptger1-4 and were genotyped in 480 asthmatics and 140 healthy controls, who were randomly recruited. Results By logistic regression analyses controlling for age and sex, 1388T > C in Ptger3 was found to be significantly associated with asthma [P=0.002, odds ratio (95% confidence interval)=0.63 (0.46-0.85) in the allele model], and this remained significant after applying the Bonferroni correction. In terms of haplotype, the frequency of the C-C-A-A haplotype in Ptger3 was significantly lower in asthmatics than in healthy controls (P=0.004). Moreover, the prevalence of this haplotype was significantly lower in moderate-to-severe asthmatics than in mild asthmatics (P=0.045; mild vs. moderate and P=0.034; mild vs. severe). However, no association was found between any genetic variation in Ptger1, Ptger2, or Ptger4 and asthma. Conclusion The present study demonstrated that genetic variations in Ptger3 are significantly associated with the risk and severity of asthma in the Korean population.X1116sciescopu

Hepatoprotective effects of blue honeysuckle on CCl4‐induced acute liver damaged mice

The objective of this study was to evaluate the hepatoprotective effects of blue honeysuckle (BH) on carbon tetrachloride (CCl4)‐induced acute hepatic damage in mice. The experiment used a total of 60 ICR mice, which were divided into six groups. Except for the intact control groups, all groups received a single intraperitoneal injection of CCl4 after a 7 day pre‐treatment period with distilled water, BH extracts, or silymarin. Twenty‐four hours after the CCl4 injection, the following observations, representative of classical oxidative stress‐mediated centrolobular necrotic acute liver injuries, were observed: decreased body weight; small nodule formation and enlargement on the gross inspections with related liver weight increase; elevation of serum AST and ALT, increases in hepatic lipid peroxidation and related depletion of endogenous antioxidants and antioxidative enzymes; centrolobular necrosis; increases in apoptotic markers, lipid peroxidation markers, and oxidative stress markers. However, liver damage was significantly inhibited by the pre‐treatment with BH extracts. The present study demonstrated that oral administration of BH extracts prior to exposure to CCl4 conferred favorable hepatoprotective effects. These results demonstrated that BHe possessed suitable properties for use as a potent hepatoprotective medicinal food