Human cytomegalovirus (CMV) is a major cause of morbidity in fetuses following intrauterine infection. The glycoprotein (g) envelope trimeric gH/gL/gO and pentameric gH/gL/pUL128/pUL130/pUL131A ...complexes are required for CMV entry into fibroblasts and endothelial/epithelial cells, respectively, and both are targets for neutralizing antibodies. The role of sequence variability among viral strains in the outcome of congenital CMV infection is controversial. Variation in the CMV UL75 gene encoding glycoprotein H (gH), the UL115 (gL), the UL74 (gO), and the UL128 locus (UL128L) encoding three structural proteins (pUL128, pUL130, and pUL131A) was determined in 82 newborns with congenital CMV infection and 113 infants with postnatal or unproven congenital CMV infection. Genotyping was performed by sequencing analysis of PCR-amplified fragments and the PCR-restriction fragment length polymorphism (RFLP) method, and the viral load was measured by quantitative real-time PCR. The obtained results demonstrated that (1) different CMV variants and mixed CMV infections can be detected in newborns infected congenitally; (2) the gH1 genotype, UL130 variant 6, and UL131A variant 1 were associated with some signs/symptoms within cohort of pediatric patients, mainly consisting of infants with symptomatic CMV infection. The results revealed that pUL130, pUL131A, and gH polymorphisms seemed to be associated with the outcome of CMV infection in infants.
Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory ...cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni's correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Toll-like receptor 9 (TLR9) recognizes non-methylated viral CpG-containing DNA and serves as a pattern recognition receptor that signals the presence of human cytomegalovirus (HCMV). Here, we present ...the genotype distribution of single-nucleotide polymorphisms (SNPs) of the TLR9 gene in infants and the relationship between TLR9 polymorphisms and HCMV infection. Four polymorphisms (-1237T/C, rs5743836; -1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) in the TLR9 gene were genotyped in 72 infants with symptomatic HCMV infection and 70 healthy individuals. SNP genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Digested fragments were separated and identified by capillary electrophoresis. The HCMV DNA copy number was measured by a quantitative real-time PCR assay. We found an increased frequency of heterozygous genotypes TLR9 -1486T/C and 2848C/T in infants with HCMV infection compared with uninfected cases. Heterozygous variants of these two SNPs increased the risk of HCMV disease in children (P = 0.044 and P = 0.029, respectively). In infants with a mutation present in at least one allele of -1486T/C and 2848C/T SNPs, a trend towards increased risk of cytomegaly was confirmed after Bonferroni's correction for multiple testing (Pc = 0.063). The rs352139 GG genotype showed a significantly reduced relative risk for HCMV infection (Pc = 0.006). In contrast, the -1237T/C SNP was not related to viral infection. We found no evidence for linkage disequilibrium with the four examined TLR9 SNPs. The findings suggest that the TLR9 -1486T/C and 2848C/T polymorphisms could be a genetic risk factor for the development of HCMV disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Human cytomegalovirus (HCMV) is the leading cause of congenital infections. The aim of our study was to determine the prevalence of genotypes based on the highly polymorphic UL146 and UL147 ...HCMV genes and the relationship between the genotype and symptoms or viral load. We analyzed samples from 121 infants with symptomatic HCMV infection, including 32 congenitally infected newborns. The G7 and G5 genotypes were predominant in postnatal infection, whereas the G1 genotype was prevalent in congenital infection. Central nervous system (CNS) damage and hepatomegaly were detected more frequently among children infected with the G1 genotype than in those infected by other genotypes. An association between the viral genotype and viruria level was found. There was a strong correlation between HCMV genotypes determined through the UL146 and UL147 sequences ( ĸ =0.794). In conclusion, we found that certain vCXCL genotypes are associated with clinical sequelae following HCMV infection.
Highlights • The distribution of TLR2 and TLR4 SNPs in patients with CMV infection was determined. • The wild-type TLR2 genotype may be a risk factor for CMV disease in adult patients. • An ...association between CMV load and the TLR4 SNP was found. • No significant differences in TLRs SNPs were observed in infants.
ABSTRACT
Background and Objective:
The course of chronic hepatitis C in children is often mild or asymptomatic, but may lead to liver cirrhosis and neoplasm. The aim of our study was retrospective ...evaluation of treatment efficacy using pegylated interferon (IFN)‐α2b with ribavirin in children and adolescents with chronic hepatitis C, both treatment naïve and re‐treated.
Methods:
The study comprised 79 patients with chronic hepatitis C ages 8 to 18 years (43 patients re‐treated; 54 infected with genotype 1 hepatitis C virus and 25 with genotype 4), treated with pegylated IFN‐α2b (1.5 μg · kg−1 · week−1) plus ribavirin (15 mg · kg−1 · day−1) for 48 weeks. The primary endpoint was sustained virologic response (SVR).
Results:
Early viral response (EVR) was observed in 43.1% and end‐of‐treatment response in 47.9% of patients. In 44.3% of patients, SVR was achieved, which was maintained for at least the next 6 months. Patients not treated before significantly more frequently attained EVR, end‐of‐treatment response, and SVR (64%, 65.6%, and 63.9%, respectively) as compared with re‐treated patients (30%, 33.3%, and 27.9%, respectively). Among 28 patients who attained EVR, 23 achieved SVR. In 2 patients, despite lack of EVR, SVR was observed. There were numerous adverse effects. They were not so severe as to discontinue therapy.
Conclusions:
Combined therapy with pegylated IFN‐α2b and ribavirin in patients with chronic hepatitis C, infected with hepatitis C virus genotypes 1 and 4, was more effective in treatment‐naïve patients (63.9%) as compared with re‐therapy cases (27.9%). SVR was maintained for at least the next 6 months in all of the patients. The applied treatment has limited efficacy and evokes numerous adverse effects; thus, search for new methods of treatment is mandatory.
Abstract Background Human cytomegalovirus (HCMV) is the most widespread cause of congenital infection. The effects of various viral strains and viral loads on the infection outcome have been under ...debate. Objectives To determine the distribution of gN variants in HCMV strains isolated from children with congenital or postnatal infection and to establish the relationship between the viral genotype, the viral load, and the sequelae. Study design The study population included congenitally HCMV-infected newborns and children with postnatal or unproven congenital HCMV infection. The genotyping was performed by RFLP analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. Results Our results demonstrated that the HCMV genotypes gN3b, gN4b, and gN4c were prevalent in the patients examined. There were no differences in the distributions of gN genotypes in the congenitally and postnatally infected children. Multiple HCMV strains were detected in both groups of children. A significant association between the HCMV gN4 genotype and the incidence of neurological disorders was observed ( p = 0.045). Our results suggest that the detection of the gN2 or the gN4 genotype may be indicative of serious manifestations in children. In contrast, the gN3b and the gN1 genotypes represent less pathogenic HCMV strains. The HCMV load in urine was significantly higher in children with congenital infection compared with children with postnatal infection. No correlation was found between the viral load and the genotype. Conclusion Our results suggest that the gN genotype may be a virological marker of symptomatic HCMV infection in newborns.
Mannose-binding lectin in chronic hepatitis C in children Dzwonek, Agnieszka Balbina; Woźniakowska-GĘsicka, Teresa; Wiśniewska-Ligier, Małgorzata
Scandinavian journal of gastroenterology,
01/2015, Letnik:
50, Številka:
10
Journal Article
Recenzirano
Objective. To investigate effect of mannose-binding lectin (MBL) genetic polymorphisms and phenotype in chronic hepatitis C and its impact on response to antiviral therapy in children. Methods. Fifty ...four children with chronic hepatitis C, aged 2.5-18 years were enrolled. Forty-five children were treated with interferon-α (IFN-α) alone (n = 2) or IFN-α and ribavirin (n = 43). Twenty-one children who responded to antiviral therapy were defined as sustained responders to therapy (IFN-SR). Before therapy, MBL genotypes and serum MBL levels (by ELISA) were determined. MBL genotype distribution and levels were correlated to disease characteristics and response to therapy. Results. Children with chronic hepatitis C who did not respond to antiviral therapy (IFN-NR) presented more frequently MBL2 polymorphisms, although this did not reach significance (p = 0.08). MBL levels were significantly lower in children classified as IFN-NR when compared to children defined as IFN-SR (1.623 ng/ml vs. 3.699 ng/ml), (p = 0.04). Serum activity levels of ALT and AST were higher in children with A/O MBL genotype when compared to group with A/A genotype (p < 0.05). Conclusions. Our findings suggest negative effect of MBL deficiency (defined by genotype and phenotype) on progression of chronic hepatitis C in children and response to antiviral therapy.
Ostre rozsiane zapalenie mózgu i rdzenia kręgowego (acute disseminated encephalomyelitis – ADEM) charakteryzuje się odczynem zapalnym i demielinizacją w obrębie ośrodkowego układu nerwowego, które są ...następstwem chorób zakaźnych lub szczepień. Występuje bardzo rzadko, częściej u dzieci niż u dorosłych, zwykle kończy się pełnym wyzdrowieniem, ale może prowadzić do zgonu lub powodować odległe następstwa. Diagnoza choroby jest trudna i wymaga głównie różnicowania ze stwardnieniem rozsianym; najbardziej pomocne dla rozpoznania jest badanie za pomocą rezonansu magnetycznego. W ostrym okresie choroby postępowanie z wyboru stanowi steroidoterapia. W pracy przedstawiono dwa przypadki ADEM (u 6-letniego chłopca i 5-letniej dziewczynki) o niejasnej etiologii, będące następstwem jałowego zapalenia opon mózgowo-rdzeniowych.
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