A key unsolved question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of acquired immunity. Insights from infections with the four seasonal human coronaviruses might ...reveal common characteristics applicable to all human coronaviruses. We monitored healthy individuals for more than 35 years and determined that reinfection with the same seasonal coronavirus occurred frequently at 12 months after infection.
Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop ...personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case–control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696–0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injury.
Idiosyncratic drug-induced liver injury is a multifactorial complex disease, in which the toxic potential of the drug, together with genetic and acquired factors and deficiencies in adaptive ...processes, which limit the extent of damage, can determine susceptibility, and make individuals unique in their development of hepatotoxicity. The aim of the present study is to analyse the genetic factors (human leukocyte antigen HLA, cytokine polymorphisms, and killer cell immunoglobulin-like receptor KIR genotype) of children who experience an episode of drug-induced liver injury.
Prospective multicentre case-control study. The subjects included in the study were 30 paediatric patients-infants and children ages between 0 and 15 years and who presented possible liver disease associated with the intake of medicines, herbal products, drugs, or toxins. As a control group, 62 subjects were selected.
Although HLAC0401 and HLADQB0603 may provide a hepatoprotective mechanism in the paediatric population, HLADQA0102 and HLA-DR12 are more commonly found in sick children and their presence may be related to liver damage. The KIR inhibitor KIR3DL1 was not present in any child in the control group.
Polymorphisms that are low producers of interleukin-10 occur more frequently in children who have experienced hepatotoxicity.
Baculoviruses (BVs) are dsDNA viruses that are pathogenic for insects. They have been used worldwide as selective bioinsecticides and for producing recombinant proteins in insect cells. Surprisingly, ...despite their widespread use in research and industry and their dissemination in the environment, the potential effects of these insect viruses on the immune responses of mammals remain totally unknown. We show in this study that BVs have strong adjuvant properties in mice, promoting potent humoral and CD8(+) T cell adaptive responses against coadministered Ag. BVs also induce the in vivo maturation of dendritic cells and the production of inflammatory cytokines. We demonstrate that BVs play a major role in the strong immunogenicity of virus-like particles produced in the BV-insect cell expression system. The presence of even small numbers of BVs among the recombinant proteins produced in the BV expression system may therefore strengthen the immunological properties of these proteins. This adjuvant behavior of BVs is mediated primarily by IFN-alphabeta, although mechanisms independent of type I IFN signaling are also involved. This study demonstrates that nonpathogenic insect viruses may have a strong effect on the mammalian immune system.
Worldwide, measures are being implemented to eradicate hepatitis B (HBV) and C (HCV) viruses, which can be transmitted from the mother during childbirth. This study aims to determine the prevalence ...of HBV and HCV in pregnant women in Spain, focusing on country of origin, epidemiological factors and risk of vertical transmission (VT).
Multicentre open-cohort study performed during 2015. HBV prevalence was determined in 21870 pregnant women and HCV prevalence in 7659 pregnant women. Epidemiological and risk factors for VT were analysed in positive women and differences between HBV and HCV cases were studied.
HBV prevalence was 0.42% (91/21870) and HCV prevalence was 0.26% (20/7659). Of the women with HBV, 65.7% (44/67) were migrants. The HBV transmission route to the mother was unknown in 40.3% of cases (27/67) and VT in 31.3% (21/67). Among risk factors for VT, 67.7% (42/62) of the women had viraemia and 14.5% (9/62) tested HBeAg-positive. All of the neonates born to HBV-positive mothers received immunoprophylaxis, and none contracted infection by VT. In 80% (16/20) of the women with HCV, the transmission route was parenteral, and nine were intravenous drug users. Viraemia was present in 40% (8/20) of the women and 10% (2/20) were HIV-coinfected. No children were infected. Women with HCV were less likely than women with HBV to breastfeed their child (65% vs. 86%).
The prevalences obtained in our study of pregnant women are lower than those previously documented for the general population. Among the women with HBV, the majority were migrants and had a maternal family history of infection, while among those with HCV, the most common factor was intravenous drug use. Despite the risk factors observed for VT, none of the children were infected. Proper immunoprophylaxis is essential to prevent VT in children born to HBV-positive women.
Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays ...heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.
NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.
Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).
The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.
The vertical transmission of hepatitis C virus (HCV‐VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyzed the role of interleukin ...28B (IL28B) in HCV‐VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited for this study: 100 were HCV‐RNA+ve / human immunodeficiency virus negative (HIV−ve), with 128 children, and 33 were HCV‐RNA−ve/HCV antibody+ve, with 43 children. The infants were tested for HCV‐RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV‐VT was assumed when children presented HCV‐RNA+ve in two subsequent blood samples. HCV‐VT‐infected infants were categorized as: (1) transient viremia with posterior HCV‐RNA−ve and without serum‐conversion; (2) persistent infection with serum‐conversion. Of the 31 mothers with CC polymorphism, 19 (61%) were HCV‐RNA+ve, whereas among the 68 mothers with non‐CC polymorphism, 56 (82%) were HCV‐RNA+ve. In all, 26 of 128 (20%) infants born to the HCV‐RNA+ve mothers acquired HCV infection, but only 9 (7%) were chronically infected. The rate of HCV‐VT was higher among the mothers with higher HCV viremia. No HCV‐VT was detected in the HCV‐RNA−ve women. Neither the mothers' nor the childrens' IL‐28 status was associated with an increased risk of HCV‐VT. The factors influencing viral clearance among the infected children were genotype non‐1 and genotype CC of IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV‐clearance in HCV genotype‐1. Conclusion: High maternal viral load is the only predictive factor of HCV‐VT. IL28B plays no role in HCV‐VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype‐1 among infected children. (HEPATOLOGY 2011;)
Viral factors are considered the best predictors of response to treatment for chronic hepatitis C (CHC), but genetic factors are known to have an important role in this respect. This paper ...investigates the relationships among the host genetic factors HLA and IL28B, viral factors, and the outcome of combination therapy.
A multicenter retrospective cohort of 428 previously untreated CHC patients was treated with pegylated interferon/ribavirin (pegIFN/RBV) for 48 weeks. In all, 378 (88%) of these patients were genotype 1 or 4, and 50 (12%) were genotype 2 or 3.
Multivariate logistic regression showed the rs12979860 CC genotype (adjusted odds ratio (aOR)=4.3, 95% confidence interval (95% CI): 2.6-7), the HLA-DQB1*0301 allele (aOR=2.08, 95% CI: 1.2-3.5) and age, viral genotype, and viral load levels to be significantly associated with sustained virological response (SVR). When the variable rs12979860 was eliminated, the area under the receiver operating characteristic (ROC) curve (AUC) decreased significantly (0.76 vs. 0.69; P=0.03). AUC values derived from viral factors were lower than those corresponding to host genetic factors (0.67 vs. 0.72, respectively; P=0.04). The HLA-DQB1*0301 and A*0201 alleles were associated with rs12979860 CC genotype and SVR (P<0.0001).
The HLA-DQB1*0301 allele and IL28B genotype are factors that are associated independently with SVR. There is a synergism between the HLA-DQB1*0301 and HLA-A*0201 alleles with polymorphism rs12979860 CC, which increases the SVR rate. IL28B genotype is the best predictor of SVR.
Heterologous production of isoprene (C
5
H
8
) hydrocarbons in cyanobacteria, emanating from sunlight, CO
2
, and water, is now attracting increasing attention. The concept entails application of an ...isoprene synthase transgene from terrestrial plants, heterologously expressed in cyanobacteria, aiming to reprogram carbon flux in the terpenoid biosynthetic pathway toward formation and spontaneous release of this volatile chemical from the cell and liquid culture. However, flux manipulations and carbon-partitioning reactions between isoprene (the product) and native terpenoid biosynthesis for cellular needs are not yet optimized for isoprene yield. The primary reactant for isoprene biosynthesis is dimethylallyl diphosphate (DMAPP), whereas both DMAPP and its isopentenyl diphosphate (IPP) isomer are needed for cellular terpenoid biosynthesis. The present work addressed the function of an isopentenyl diphosphate (IPP) isomerase in cyanobacteria and its role in carbon partitioning between IPP and DMAPP, both of which serve, in variable ratios, as reactants for the synthesis of different cellular terpenoids. The work was approached upon the heterologous expression in
Synechocystis
of the “isopentenyl diphosphate isomerase” gene (
FNI
) from
Streptococcus pneumoniae,
using isoprene production as a “reporter process” for substrate partitioning between DMAPP and IPP. It is shown that transgenic expression of the
FNI
gene in
Synechocystis
resulted in a 250 % increase in the “reporter isoprene” rate and yield, suggesting that the FNI isomerase shifted the endogenous DMAPP-IPP steady-state pool size toward DMAPP, thereby enhancing rates and yield of isoprene production. The work provides insight into the significance and functional role of the IPP isomerase in these photosynthetic microorganisms.
The progression of chronic hepatitis B (CHB) is related to fibrosis and to the emergence of intrahepatic anomalous vascular structures. Hepatitis B virus (HBV) X protein transactivator (HBx) may play ...a significant role in both processes. To analyze how HBV induces vascular growth and remodeling in vivo, we assessed the expression of angiopoietin-2 (Ang2) in liver biopsies from CHB patients by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry because of the relevant role of Ang2 in vascular development, remodeling, and tumor promotion. In addition, we analyzed the influence of HBx in the expression of Ang2 in HBx-expressing hepatocyte cell lines and in hepatic stellate cells stimulated with conditional medium from HBx-hepatocytes. Ang2 expression was clearly up-regulated at both mRNA and protein levels in the liver of CHB patients, showing an intense staining of inflammatory infiltrates and vascular structures at inflamed portal areas. HBx-expressing hepatocytes and stimulated stellate cells showed a significant induction of Ang2 expression. PI3K inhibitor and antioxidants repressed the 64-kd Ang2 form but further enhanced the inflammation-related 50-kd molecular species. Therefore, HBx could account for the induction of Ang2 observed in CHB, especially the 50-kd form, contributing to pathological angiogenesis and hepatocellular carcinoma progression.
PDF
