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1.
Protein Pept Lett ; 31(4): 305-311, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38644721

RESUMO

BACKGROUND: Protease 3C (3Cpro) is the only protease encoded in the human hepatitis A virus genome and is considered as a potential target for antiviral drugs due to its critical role in the viral life cycle. Additionally, 3Cpro has been identified as a potent inducer of ferroptosis, a newly described type of cell death. Therefore, studying the molecular mechanism of 3Cpro functioning can provide new insights into viral-host interaction and the biological role of ferroptosis. However, such studies require a reliable technique for producing the functionally active recombinant enzyme. OBJECTIVE: Here, we expressed different modified forms of 3Cpro with a hexahistidine tag on the N- or C-terminus to investigate the applicability of immobilized metal Ion affinity chromatography (IMAC) for producing 3Cpro. METHODS: We expressed the proteins in Escherichia coli and purified them using IMAC, followed by gel permeation chromatography. The enzymatic activity of the produced proteins was assayed using a specific chromogenic substrate. RESULTS: Our findings showed that the introduction and position of the hexahistidine tag did not affect the activity of the enzyme. However, the yield of the target protein was highest for the variant with seven C-terminal residues replaced by a hexahistidine sequence. CONCLUSION: We demonstrated the applicability of our approach for producing recombinant, enzymatically active 3Cpro.


Assuntos
Proteases Virais 3C , Cromatografia de Afinidade , Escherichia coli , Histidina , Oligopeptídeos , Histidina/genética , Histidina/metabolismo , Histidina/química , Proteases Virais 3C/química , Proteases Virais 3C/metabolismo , Humanos , Oligopeptídeos/genética , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Virais/genética , Proteínas Virais/química , Proteínas Virais/metabolismo , Proteínas Virais/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/biossíntese , Vírus da Hepatite A Humana/genética , Vírus da Hepatite A Humana/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Expressão Gênica
3.
Anal Methods ; 15(43): 5813-5822, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37870419

RESUMO

Picornavirus hepatitis A virus (HAV) is a common cause of hepatitis worldwide. It is spread primarily through contaminated food and water or person-to-person contact. HAV I has been identified as the most common type of human HAV infection. Here, we have developed a cell-free toehold switch sensor for HAV I detection. We screened 10 suitable toehold switch sequences using NUPACK software, and the VP1 gene was used as the target gene. The optimal toehold switch sequence was selected by in vivo expression. The best toehold switch concentration was further found to be 20 nM in a cell-free system. 5 nM trigger RNA activated the toehold switch to generate visible green fluorescence. The minimum detection concentration decreased to 1 pM once combined with NASBA. HAV I trigger RNA could be detected accurately with excellent specificity. In addition, the cell-free toehold switch sensor was verified in HAV I entities. The successful construction of the cell-free toehold switch sensor provided a convenient, rapid, and accurate method for HAV I on-site detection, especially in developing countries, without the involvement of expensive facilities and additional professional operators.


Assuntos
Vírus da Hepatite A , Hepatite A , Humanos , Vírus da Hepatite A/genética , Hepatite A/diagnóstico , Vírus da Hepatite A Humana/genética , RNA
4.
Viruses ; 15(2)2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36851763

RESUMO

Hepatitis E virus (HEV) has emerged as a public health concern in Brazil. From the first identification and characterization of porcine and human HEV-3 strains in the 2000s, new HEV subtypes have been identified from animal, human, and environmental isolates. As new potential animal reservoirs have emerged, there is a need to compile evidence on the zoonotic dissemination of the virus in animal hosts and the environment. The increasing amount of seroprevalence data on sampled and randomly selected populations must be systematically retrieved, interpreted, and considered under the One Health concept. This review focused on HEV seroprevalence data in distinct animal reservoirs and human populations reported in the last two decades. Furthermore, the expertise with experimental infection models using non-human primates may provide new insights into HEV pathogenesis, prevention, and environmental surveillance.


Assuntos
Vírus da Hepatite E , Animais , Suínos , Brasil/epidemiologia , Vírus da Hepatite E/genética , Estudos Soroepidemiológicos , Monitoramento Ambiental , Vírus da Hepatite A Humana
5.
Indian J Med Microbiol ; 43: 96-100, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36481121

RESUMO

With the changing hepatitis A epidemiology in India, focal viral outbreaks are being reported from different parts of the country. This study presents Hepatitis A Virus (HAV) strain characterization (period 2009-2020) from 18 states of India. For that, blood and stool samples (n â€‹= â€‹280) were screened for HAV RNA and sequences for 5'non-coding and VP3 regions were generated from positive samples (n â€‹= â€‹68). Presence of a single IIIA genotype in all samples indicated IIIA being the only HAV genotype currently circulating in India. Interestingly, it was evident that these strains form two distinct groups suggesting independent evolution of these two clusters.


Assuntos
Vírus da Hepatite A Humana , Hepatite A , Vírus da Hepatite A Humana/classificação , Vírus da Hepatite A Humana/genética , Vírus da Hepatite A Humana/isolamento & purificação , Índia/epidemiologia , Genótipo , Filogenia , Fezes/química , Fezes/virologia , Hepatite A/sangue , Hepatite A/epidemiologia , Hepatite A/virologia , Humanos , RNA Viral/análise
6.
Viruses ; 13(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34960739

RESUMO

As South Africa transitions from endemic to intermediate endemicity, hepatitis A surveillance needs strengthening to monitor trends in disease incidence and to identify outbreaks. We used passive laboratory-based surveillance data from the National Health Laboratory Services to calculate national hepatitis A incidence and to establish thresholds for outbreaks. Incidence was calculated by age and geographic location. The static threshold used two or three standard deviations (SDs) above the mean hepatitis A incidence in 2017-2019, and a cumulative summation (CuSum2) threshold used three SDs above the mean of the preceding seven months. These thresholds were applied to hepatitis A data for 2020. From 2017 to 2020, the mean incidence of hepatitis A IgM was 4.06/100,000 and ranged from 4.23 to 4.85/100,000 per year. Hepatitis A incidence was highest in the Western Cape province (WCP) (7.00-10.92/100,000 per year). The highest incidence was in the 1-9-year-olds. The incidence of hepatitis A in 2020 exceeded the static threshold in two districts of the WCP: Cape Winelands in January and Overberg district in August. The provincial incidence did not exceed the static and CuSum2 thresholds. District-level analysis using either threshold was sensitive enough to monitor trends and to alert district health authorities, allowing early outbreak responses.


Assuntos
Surtos de Doenças , Monitoramento Epidemiológico , Hepatite A/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Vírus da Hepatite A Humana/imunologia , Humanos , Imunoglobulina M/sangue , Incidência , Masculino , Pessoa de Meia-Idade , África do Sul/epidemiologia , Adulto Jovem
7.
Sci Rep ; 11(1): 4778, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637853

RESUMO

This study determined the prevalence of total hepatitis A antibody (anti-HAV) among 5-7 years old children and their mothers in the whole Cambodia, using a nationwide study, and examined the differences between the two cohorts. A total of 4535 dried blood spot-driven (DBS) samples (2021 mothers and their 2514 children of 5-7 years old) and the concomitant 922 whole blood samples (subset of the whole participants) were collected using a multistage random sampling strategy throughout Cambodia in 2017. Total anti-HAV was detected using the chemiluminescence enzyme immunoassay method. Compared to gold standard whole blood samples, the sensitivity and specificity of DBS mediated anti-HAV detection were 94.8% and 98%, respectively. Total anti-HAV prevalence among mothers was 91.2% (95%CI: 90.0-92.5%), and that of their children was 31.5% (95%CI: 29.7-33.3%). In our study, the low prevalence of total anti-HAV among children indicates the country's improvement of safe water and food supply, hygiene and sanitation. If the hygiene and sanitation are consistently improved in Cambodia, the prevalence might be no longer increased when the children become adults.


Assuntos
Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A Humana/isolamento & purificação , Hepatite A/sangue , Camboja/epidemiologia , Criança , Pré-Escolar , Feminino , Hepatite A/epidemiologia , Hepatite A/imunologia , Anticorpos Anti-Hepatite A/imunologia , Vírus da Hepatite A Humana/imunologia , Humanos , Masculino , Prevalência , Estudos Soroepidemiológicos
8.
Arch Virol ; 166(3): 789-799, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33459883

RESUMO

Hepatitis A virus (HAV), a unique hepatotropic human picornavirus, is the causative agent of acute hepatitis A in humans. Some studies have shown that HAV antagonizes the innate immune response by disrupting interferon-beta (IFN-ß) signaling by viral proteins. However, whether microRNAs (miRNAs), a class of non-coding RNAs, are involved in the antagonism of IFN-ß induction upon HAV infection is still unclear. In this study, we investigated the effects and mechanisms by which HAV-induced miRNAs antagonize IFN-ß signaling. A variety of analytical methods, including miRNA microarray, RT-qPCR, dual-luciferase reporter assay, and Western blotting, were performed using HAV-infected cells. The results indicated that HAV infection upregulates the expression of hsa-miR-146a-5p, which in turn partially suppresses the induction of IFN-ß synthesis, thereby promoting viral replication. Mechanistically, TRAF6 (TNF receptor-associated factor 6), a key adaptor protein in the RIG-I/MDA5-mediated IFN-I signaling pathway, is targeted and degraded by hsa-miR-146a-5p. As TRAF6 is necessary for IFN-ß induction, inhibition of this protein attenuates IFN-ß signaling. Taken together, the results from this study indicated that HAV disrupts RIG-I/MDA5-mediated IFN-I signaling partially through the cleavage of the essential adaptor molecule TRAF6 via hsa-miR-146a-5p.


Assuntos
Vírus da Hepatite A Humana/crescimento & desenvolvimento , Interferon gama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/genética , Linhagem Celular , Regulação da Expressão Gênica , Hepatite A/patologia , Vírus da Hepatite A Humana/genética , Humanos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Replicação Viral
9.
Eur J Clin Microbiol Infect Dis ; 40(2): 335-344, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32940811

RESUMO

To explore the epidemiology and clinical course of hepatitis A virus (HAV) infections at the Vienna General Hospital. We retrospectively identified patients who were tested positive for HAV-IgM at the Vienna General Hospital form Q1/2008 to Q3/2018. Our definition of severe HAV infection was AST and/or ALT > 5 × above the upper limit of normal (ULN); and liver dysfunction as (i) hepatic encephalopathy or ammonia > 100 µmol/L, (ii) coagulopathy with INR > 1.5, or (iii) jaundice with bilirubin > 5 mg/dL. A total of 578 HAV-IgM (+) were identified, including 31 (5.4%) and 38 (6.6%) without and with liver dysfunction, respectively. A proportional increase in severe HAV cases with and without liver dysfunction occurred in 2016/2017 with (21.5% (vs. 8.0% in the years before; p < 0.001). Thirty-seven (53.6%) patients with severe HAV were hospitalized, 6 (9%) required ICU support, and one patient received liver transplantation within 30 days. Patients with severe HAV and liver dysfunction were more often male (60.5 vs. 43.1%, p = 0.055) and younger (31.5 vs. 63 years, p < 0.001) as compared with other HAV-IgM (+) cases. The observed increase of severe HAV infections in Vienna in 2017 among young males, coincided with a multinational HAV outbreak among MSM. Our data suggests a higher likelihood of severe courses of hepatitis A in MSM. Vaccination against HAV should be recommended for risk groups.


Assuntos
Surtos de Doenças , Hepatite A/epidemiologia , Adulto , Áustria/epidemiologia , Feminino , Vírus da Hepatite A Humana/isolamento & purificação , Hospitais Gerais , Hospitais Urbanos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Minorias Sexuais e de Gênero
10.
Hepatology ; 73(4): 1251-1260, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32592242

RESUMO

BACKGROUND AND AIMS: China has conducted surveillance for hepatitis A since 1990, and hepatitis A was highly-to-intermediately endemic in 1992 when a Chinese hepatitis A vaccine (HepA) was licensed and introduced as a family-pay vaccine. In 2008, HepA was introduced into the Expanded Program on Immunization as a free childhood vaccine. APPROACH AND RESULTS: Three nationally representative surveys conducted in 1992, 2006, and 2014 assessed hepatitis B serology. The 1992 survey included hepatitis A virus (HAV) serology, and we tested sera from the 2006 and 2014 surveys for HAV antibodies. We used surveillance, seroprevalence, and vaccination status data to describe the changing epidemiology of hepatitis A in China from 1990 through 2014. Before HepA licensure, anti-HAV seroprevalence was 60% at 4 years of age, 70% at 10 years, and 90% at 59 years; incidence was 52/100,000 and peaked at 4 years. In 2006, after >10 years of private sector vaccination, HepA coverage was <30% among children <5 years, and incidence was 5.4/100,000 with a peak at 10 years. In 2014, coverage was >90% among children under 5 years; incidence was 1.9/100,000. Individuals born before the national introduction of HepA (1988-2004) had lower anti-HAV seroprevalence than earlier and later birth cohorts. CONCLUSIONS: The incidence of hepatitis A declined markedly following HepA introduction and improvement of sanitation and hygiene. The emerging epidemiology is consistent with disease-induced immunity having been replaced by vaccine-induced immunity, resulting in a low incidence of hepatitis A. Catch-up HepA campaigns to close the immunity gap among the 1998-2004 birth cohorts should be considered.


Assuntos
Vacinas contra Hepatite A/uso terapêutico , Vírus da Hepatite A Humana/imunologia , Hepatite A/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Notificação de Doenças/estatística & dados numéricos , Feminino , Hepatite A/imunologia , Hepatite A/prevenção & controle , Anticorpos Anti-Hepatite A/imunologia , Humanos , Incidência , Lactente , Masculino , Vacinação em Massa/estatística & dados numéricos , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Estudos Soroepidemiológicos , Adulto Jovem
11.
PLoS One ; 15(12): e0240339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33306686

RESUMO

BACKGROUND: Hepatitis A virus (HAV) infection is one of the major causes of acute viral hepatitis. HAV genotypes and its genetic diversity is rarely investigated in our region as well as worldwide. AIMS: The aims of the present study were to determine the HAV genotypes and its risk factors and to investigate the genetic diversity of the HAV isolates in the West Bank, Palestine. STUDY DESIGN: A cohort of 161 clinically and laboratory-confirmed HAV (IgM-positive) cases and 170 apparently healthy controls from all the districts of the West Bank, Palestine during the period of 2014 to 2016 were tested for HAV infection using IgM antibodies, RT-PCR and sequence analysis of the VP3/VP1 junction region of the HAV genome. Phylogenetic analysis, genetic diversity and haplotypes analysis were used to characterize the VP3/VP1 sequences. RESULTS: All the 34 sequences of the HAV were found to be of HAV-IB sub-genotype. The phylogenetic analysis showed four main clusters with cluster III exclusively consisting of 18 Palestinian isolates (18/23-78%), but with weak bootstrap values. A high haplotype diversity (Hd) and low nucleotide diversity (π) were observed. Cluster III showed high number of haplotypes (h = 8), but low haplotype (gene) diversity (Hd = 0.69). A total of 28 active haplotypes with some consisting of more than one sequence were observed using haplotype network analysis. The Palestinian haplotypes are characterized by closely related viral haplotypes with one SNV away from each other which ran parallel to cluster III in the phylogenetic tree. A smaller Palestinian haplotype (4 isolates) was three SNVs away from the major haplotype cluster (n = 10) and closer to others haplotypes from Iran, Spain, and South Africa. Young age, low level of parent's education, infrequent hand washing before meals, and drinking of un-treated water were considered the major HAV risk factors in the present study. CONCLUSION: Haplotype network analysis revealed haplotype variation among the HAV Palestinian sequences despite low genetic variation and nucleotide diversity. In addition, this study reconfirmed that age and parent's level of education as HAV risk factors, while hand washing and treating drinking water as protective factors.


Assuntos
Vírus da Hepatite A Humana/genética , Hepatite A/epidemiologia , Hepatite A/virologia , Adolescente , Adulto , Fatores Etários , Substituição de Aminoácidos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/isolamento & purificação , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Escolaridade , Feminino , Genoma Viral/genética , Haplótipos , Hepatite A/sangue , Hepatite A/diagnóstico , Vírus da Hepatite A Humana/isolamento & purificação , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Oriente Médio/epidemiologia , Epidemiologia Molecular , Filogenia , Polimorfismo de Nucleotídeo Único , RNA Viral/genética , RNA Viral/isolamento & purificação , Fatores de Risco , Análise de Sequência de DNA , Adulto Jovem
12.
BMJ Open ; 10(6): e036727, 2020 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-32513893

RESUMO

OBJECTIVES: Hepatitis A incidence in Korea has dramatically increased in recent years. Individuals in their twenties and thirties, who account for majority of the workforce in Korea, are particularly susceptible to infection owing to a low seroprevalence of anti-hepatitis A virus (anti-HAV) immunoglobulin G (IgG). This study aimed to identify behavioural and occupational factors related to anti-HAV IgG seropositivity. DESIGN: Cross-sectional study. SETTING: A large university hospital in Seoul, Korea. PARTICIPANTS: Workers in formal employment having an annual routine health screening. PRIMARY OUTCOME MEASURE: Anti-HAV IgG seropositivity. RESULTS: Of 131 711 individuals who had an annual health screening at the study hospital in 2018, 68 612 met the inclusion criteria and were included in the analysis. Study participants were predominantly men (64.3%) and in their thirties (55.3%). The overall seroprevalence of anti-HAV IgG was 36.2%. In multivariate analyses, anti-HAV IgG seropositivity was independently associated with working in a workplace with ≥2 health managers (vs no health manager, adjusted OR 1.32, 95% CI 1.22 to 1.43); age 40-49 years (vs 20-29 years, OR 2.51, 95% CI 2.36 to 2.68); female sex (OR 1.54, 95% CI 1.48 to 1.59); experience of any general disease (vs no general disease history, OR 1.19, 95% CI 1.14 to 1.25), obesity (vs normal weight, OR 0.91, 95% CI 0.86 to 0.97); and hepatitis B antibody seropositivity (OR 2.39, 95% CI 2.31 to 2.49). CONCLUSIONS: The low prevalence of anti-HAV IgG seropositivity points to a need for implementation of workplace-based hepatitis A vaccine programmes. To promote workers' health and prevent hepatitis A outbreaks, occupational health managers, healthcare providers and policy-makers should focus on individuals who are susceptible to HAV, such as young men.


Assuntos
Pessoal de Saúde , Hepatite A/epidemiologia , Doenças Profissionais/epidemiologia , Adulto , Estudos Transversais , Feminino , Hepatite A/sangue , Hepatite A/prevenção & controle , Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A Humana/imunologia , Hospitais Universitários , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/prevenção & controle , República da Coreia/epidemiologia , Estudos Soroepidemiológicos , Adulto Jovem
13.
Nat Commun ; 11(1): 1677, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245952

RESUMO

Human stem cell-derived hepatocyte-like cells (HLCs) offer an attractive platform to study liver biology. Despite their numerous advantages, HLCs lack critical in vivo characteristics, including cell polarity. Here, we report a stem cell differentiation protocol that uses transwell filters to generate columnar polarized HLCs with clearly defined basolateral and apical membranes separated by tight junctions. We show that polarized HLCs secrete cargo directionally: Albumin, urea, and lipoproteins are secreted basolaterally, whereas bile acids are secreted apically. Further, we show that enterically transmitted hepatitis E virus (HEV) progeny particles are secreted basolaterally as quasi-enveloped particles and apically as naked virions, recapitulating essential steps of the natural infectious cycle in vivo. We also provide proof-of-concept that polarized HLCs can be used for pharmacokinetic and drug-drug interaction studies. This novel system provides a powerful tool to study hepatocyte biology, disease mechanisms, genetic variation, and drug metabolism in a more physiologically relevant setting.


Assuntos
Técnicas de Cultura de Células/métodos , Polaridade Celular , Hepatócitos/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Antivirais/farmacologia , Diferenciação Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Vírus da Hepatite A Humana/fisiologia , Vírus da Hepatite E/fisiologia , Hepatócitos/ultraestrutura , Hepatócitos/virologia , Humanos , Fígado/citologia , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Microscopia Eletrônica de Transmissão , Estudo de Prova de Conceito , Vírion/metabolismo , Liberação de Vírus , Replicação Viral
14.
J Hepatol ; 73(3): 640-650, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32247824

RESUMO

BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in the human liver, can be activated by cytokines during viral infection without TCR stimulation. Here, we examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. We also examined the phenotype and function of MAIT cells from patients with acute viral hepatitis. METHODS: We obtained liver sinusoidal mononuclear cells from donor liver perfusate during liver transplantation and examined the effect of various cytokines on liver MAIT cells using flow cytometry and in vitro cytotoxicity assays. We also obtained peripheral blood and liver-infiltrating T cells from patients with acute hepatitis A (AHA) and examined the phenotype and function of MAIT cells using flow cytometry. RESULTS: IL-15-stimulated MAIT cells exerted granzyme B-dependent innate-like cytotoxicity in the absence of TCR/MR1 interaction. PI3K-mTOR signaling, NKG2D ligation, and CD2-mediated conjugate formation were critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with AHA exhibited activated and cytotoxic phenotypes with higher NKG2D expression. The innate-like cytotoxicity of MAIT cells was significantly increased in patients with AHA and correlated with serum alanine aminotransferase levels. CONCLUSIONS: Taken together, the results demonstrate that liver MAIT cells activated by IL-15 exert NKG2D-dependent innate-like cytotoxicity in the absence of TCR/MR1 engagement. Furthermore, the innate-like cytotoxicity of MAIT cells is associated with liver injury in patients with AHA, suggesting that MAIT cells contribute to immune-mediated liver injury. LAY SUMMARY: Immune-mediated liver injury commonly occurs during viral infections of the liver. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the human liver. Herein, we have identified a mechanism by which MAIT cells circumvent conventional T cell receptor interactions to exert cytotoxicity. We show that this innate-like cytotoxicity is increased during acute hepatitis A virus infection and correlates with the degree of hepatocyte injury.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Vírus da Hepatite A Humana , Hepatite A/sangue , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunidade Inata/efeitos dos fármacos , Interleucina-15/farmacologia , Fígado/imunologia , Doadores Vivos , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Doença Aguda , Adulto , Células Cultivadas , Feminino , Hepatite A/virologia , Humanos , Células Matadoras Naturais/imunologia , Transplante de Fígado/métodos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
15.
J Hepatol ; 72(6): 1170-1181, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31987989

RESUMO

BACKGROUND & AIMS: Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. METHODS: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. RESULTS: Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. CONCLUSIONS: Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. LAY SUMMARY: The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Vírus da Hepatite A Humana , Hepatite A/imunologia , Cadeias alfa de Integrinas/metabolismo , Lectinas Tipo C/metabolismo , Cirrose Hepática/imunologia , Fígado/imunologia , Transdução de Sinais/imunologia , Doença Aguda , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Doadores de Sangue , Células Cultivadas , Feminino , Voluntários Saudáveis , Hepatite A/patologia , Humanos , Memória Imunológica , Indanos/farmacologia , Cirrose Hepática/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Transcriptoma , Regulação para Cima/genética
17.
Infect Disord Drug Targets ; 20(5): 748-751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31595854

RESUMO

INTRODUCTION: The aim of this study was to determine the prevalence of exposure to hepatitis A by means of serologic markers in chronic hepatitis B patients, with the secondary aim of finding the best prevention method for hepatitis A infection in susceptible groups of our setting. METHODS: During the period between 2016 and 2017, we recruited 403 hepatitis B patients aged more than 14 years and regularly attending the infectious diseases clinic at a referral university hospital, Tehran, Iran. A blood sample was collected from all the patients and tested for hepatitis A IgG. The data was analyzed by SPSS v.19. RESULTS: Although none of the patients had previously received hepatitis A vaccine, the results for serologic level of hepatitis A IgG, demonstrated positive results in 379 (94%) cases. The mean age of patients with negative and positive IgG was 29.17 and 42.46 years, respectively; the difference was statistically significant (P≤0.001). The majority of seronegative patients were young adults aged < 25 years and 25 to 35 years (P <0.001). CONCLUSION: Seroprevalence of hepatitis A in chronic HBV patients in Iran is high. As HBV infected patients younger than 35 years could be seronagative for HAV infection, evaluation of these patients for HAV infection and vaccination of seronegative patients would be a reasonable approach.


Assuntos
Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A Humana/imunologia , Hepatite A/epidemiologia , Hepatite B Crônica/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Estudos Transversais , Feminino , Hepatite B Crônica/imunologia , Hospitais Universitários , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Soroepidemiológicos , Adulto Jovem
19.
Med. leg. Costa Rica ; 36(2): 101-107, sep.-dic. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1040450

RESUMO

Resumen El virus de la hepatitis A ha estado clásicamente relacionado con el mecanismo de transmisión fecal-oral, característica de países endémicos. El aumento de las condiciones higiénicas en nuestro entorno había supuesto una importante disminución de los casos de infección por estos patógenos. Sin embargo, en la actualidad, su epidemiología esta cambiando debido a nuevas vías de contagio en Europa. En el caso de la hepatitis A, están aumentando los casos debidos a la transmisión por vía sexual, especialmente en hombres que tienen sexo con hombres. Los cambios descritos deberían promover la implantación de nuevas estrategias de diagnóstico, manejo y prevención. La hepatitis aguda por virus de hepatitis A usualmente sigue un curso corto, benigno y autolimitado sin ocasionar una hepatitis crónica, sin embargo en algunos casos puede manifestarse mediante formas atípicas.


Abstract Hepatitis A virus has been classically linked to the fecal-oral transmission mechanism, characteristic of endemic countries. The increase in hygiene conditions in our environment had led to a significant decrease in cases of infection by these pathogens. However, the epidemiology of these infections is currently changing due to new routes of transmission in Europe. In the case of hepatitis A, cases due to sexual transmission are increasing, especially among men who have sex with men. The changes described should promote the implementation of new strategies for the diagnosis, management and prevention of these diseases. Acute hepatitis due to the hepatitis A virus usually has a short, benign and self-limited course, without causing chronic hepatitis. However, some cases have an atypical presentation.


Assuntos
Humanos , Vírus da Hepatite A Humana , Vírus da Hepatite A , Hepatite A/diagnóstico , Hepatite A/epidemiologia , Hepatite Viral Humana
20.
Vaccine ; 37(44): 6648-6655, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31548013

RESUMO

INTRODUCTION: Infection with hepatitis A virus (HAV) during pregnancy, although uncommon, is associated with gestational complications and pre-term labor. Hepatitis A vaccine (HepA) is recommended for anyone at increased risk for contracting hepatitis A, including women at risk who are also pregnant. Limited data are available on the safety of maternal HepA vaccination. OBJECTIVES: Assess the frequency of maternal HepA receipt and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. METHODS: A retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live births from 2004 through 2015 was included. Pregnancies with HepA exposure were compared to those with other vaccine exposures, and to those with no vaccine exposures. Risk factors for contracting hepatitis A were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were evaluated according to maternal HepA exposure status. Adjusted odds ratio (OR) were used to describe the association. RESULTS: Among 666,233 pregnancies in the study period, HepA was administered at a rate of 1.7 per 1000 (n = 1140), most commonly within the first six weeks of pregnancy. Less than 3% of those exposed to HepA during pregnancy had an ICD-confirmed risk factor. There were no significant associations between HepA exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, and low birthweight. There was a statistically significant association between HepA exposure during pregnancy and small-for-gestational age (SGA) infants (aOR 1.32, [95% CI 1.09, 1.60], p = 0.004). CONCLUSIONS: The rate of maternal HepA vaccination was low and rarely due to documented risk factors for vaccination. HepA vaccination during pregnancy was not associated with an increased risk for a range of adverse events examined among pregnancies resulting in live births, but an identified association between maternal HepA and SGA infant outcomes, while likely due to unmeasured confounding, warrants further exploration.


Assuntos
Vacinas contra Hepatite A/administração & dosagem , Vacinas contra Hepatite A/efeitos adversos , Vírus da Hepatite A Humana/imunologia , Hepatite A/epidemiologia , Hepatite A/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Adolescente , Adulto , Feminino , Vacinas contra Hepatite A/imunologia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Resultado da Gravidez , Vigilância em Saúde Pública , Estudos Retrospectivos , Vacinação , Adulto Jovem
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