Publications by authors named "Thomas F Baumert"

298 Publications

Profibrotic Signaling and HCC Risk during Chronic Viral Hepatitis: Biomarker Development.

J Clin Med 2021 Mar 2;10(5). Epub 2021 Mar 2.

Université de Strasbourg, 67000 Strasbourg, France.

Despite breakthroughs in antiviral therapies, chronic viral hepatitis B and C are still the major causes of liver fibrosis and hepatocellular carcinoma (HCC). Importantly, even in patients with controlled infection or viral cure, the cancer risk cannot be fully eliminated, highlighting a persisting oncogenic pressure imposed by epigenetic imprinting and advanced liver disease. Reliable and minimally invasive biomarkers for early fibrosis and for residual HCC risk in HCV-cured patients are urgently needed. Chronic infection with HBV and/or HCV dysregulates oncogenic and profibrogenic signaling within the host, also displayed in the secretion of soluble factors to the blood. The study of virus-dysregulated signaling pathways may, therefore, contribute to the identification of reliable minimally invasive biomarkers for the detection of patients at early-stage liver disease potentially complementing existing noninvasive methods in clinics. With a focus on virus-induced signaling events, this review provides an overview of candidate blood biomarkers for liver disease and HCC risk associated with chronic viral hepatitis and epigenetic viral footprints.
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http://dx.doi.org/10.3390/jcm10050977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957739PMC
March 2021

Circadian regulation of SARS-CoV-2 infection in lung epithelial cells.

bioRxiv 2021 Mar 21. Epub 2021 Mar 21.

The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme (ACE2) , and infection can result in pneumonia and acute respiratory dist ress syndrome. Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection . Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication and elevated inflammatory responses leading to more severe bronchitis , highlighting the impact of circadian pathways in respiratory function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19.
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http://dx.doi.org/10.1101/2021.03.20.436163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987021PMC
March 2021

Circadian control of hepatitis B virus replication.

Nat Commun 2021 03 12;12(1):1658. Epub 2021 Mar 12.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.
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http://dx.doi.org/10.1038/s41467-021-21821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955118PMC
March 2021

Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses.

Life (Basel) 2021 Feb 16;11(2). Epub 2021 Feb 16.

INSERM, CHU Limoges, University of Limoges, RESINFIT, U1092, 87000 Limoges, France.

Herpesviruses are the causative agents of several diseases. Infections are generally mild or asymptomatic in immunocompetent individuals. In contrast, herpesvirus infections continue to contribute to significant morbidity and mortality in immunocompromised patients. Few drugs are available for the treatment of human herpesvirus infections, mainly targeting the viral DNA polymerase. Moreover, no successful therapeutic options are available for the Epstein-Barr virus or human herpesvirus 8. Most licensed drugs share the same mechanism of action of targeting the viral polymerase and thus blocking DNA polymerization. Resistances to antiviral drugs have been observed for human cytomegalovirus, herpes simplex virus and varicella-zoster virus. A new terminase inhibitor, letermovir, recently proved effective against human cytomegalovirus. However, the letermovir has no significant activity against other herpesviruses. New antivirals targeting other replication steps, such as capsid maturation or DNA packaging, and inducing fewer adverse effects are therefore needed. Targeting capsid assembly or DNA packaging provides additional options for the development of new drugs. In this review, we summarize recent findings on capsid assembly and DNA packaging. We also described what is known about the structure and function of capsid and terminase proteins to identify novels targets for the development of new therapeutic options.
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http://dx.doi.org/10.3390/life11020150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920273PMC
February 2021

Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease.

Front Immunol 2020 5;11:624034. Epub 2021 Feb 5.

INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.

A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
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http://dx.doi.org/10.3389/fimmu.2020.624034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892431PMC
February 2021

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter.

J Hepatol 2021 Jan 29. Epub 2021 Jan 29.

Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. Electronic address:

Background & Aims: Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication.

Methods: Using cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle.

Results: Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family.

Conclusions: Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection.

Lay Summary: Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets.
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http://dx.doi.org/10.1016/j.jhep.2020.12.034DOI Listing
January 2021

Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure.

Pathogens 2021 Jan 7;10(1). Epub 2021 Jan 7.

Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Inserm U1110, 67000 Strasbourg, France.

Chronic hepatitis C (CHC) is a major cause of hepatocellular carcinoma (HCC) worldwide. While directly acting antiviral (DAA) drugs are now able to cure virtually all hepatitis C virus (HCV) infections, even in subjects with advanced liver disease, what happens to the liver and progression of the disease after DAA-induced cure of viremia is only beginning to emerge. Several large-scale clinical studies in different patient populations have shown that patients with advanced liver disease maintain a risk for developing HCC even when the original instigator, the virus, is eliminated by DAAs. Here we review emerging studies derived from multiple, complementary experimental systems involving patient liver tissues, human liver cell cultures, human liver slice cultures, and animal models, showing that HCV infection induces epigenetic, signaling, and gene expression changes in the liver associated with altered hepatic innate immunity and liver cancer risk. Of critical importance is the fact that these virus-induced abnormalities persist after DAA cure of HCV. These nascent findings portend the discovery of pathways involved in post-HCV immunopathogenesis, which may be clinically actionable targets for more comprehensive care of DAA-cured individuals.
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http://dx.doi.org/10.3390/pathogens10010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825776PMC
January 2021

Liver disease and COVID-19: from Pathogenesis to Clinical Care.

Hepatology 2020 Dec 17. Epub 2020 Dec 17.

Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that emerged in late 2019 is posing an unprecedented challenge to global health. COVID-19, the clinical disease caused by SARS-CoV-2 has a variable presentation ranging from asymptomatic infection to life-threatening acute respiratory distress syndrome and multi-organ failure. Liver involvement is common during COVID-19 and exhibits a spectrum of clinical manifestations from asymptomatic elevations of liver function tests to hepatic decompensation. The presence of abnormal liver tests has been associated with a more severe presentation of COVID-19 disease and overall mortality. Although SARS-CoV-2 RNA has been detected in the liver of COVID-19 patients, it remains unclear whether SARS-CoV-2 productively infects and replicates in liver cells and has a direct liver-pathogenic effect. The cause of liver injury in COVID-19 can be attributed to multiple factors including virus-induced systemic inflammation, hypoxia, hepatic congestion and drug induced liver disease. Among patients with cirrhosis, COVID-19 has been associated with hepatic decompensation and liver-related mortality. Additionally, COVID-19's impact on healthcare resources can adversely affect delivery of care and outcomes of patients with chronic liver disease. Understanding the underlying mechanisms of liver injury during COVID-19 will be important in the management of COVID-19 patients, especially those with advanced liver disease. This review summarizes our current knowledge of SARS-CoV-2 virus-host interactions in the liver as well the clinical impact of liver disease in COVID-19.
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http://dx.doi.org/10.1002/hep.31684DOI Listing
December 2020

The Nobel Prize in Medicine 2020 for the Discovery of Hepatitis C Virus: Transforming Hepatology.

Authors:
Thomas F Baumert

J Hepatol 2020 12;73(6):1303-1305

Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Universitaire de France, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.10.017DOI Listing
December 2020

Silencing of the HBV episome through degradation of HBx protein: Towards functional cure?

J Hepatol 2021 Mar 10;74(3):497-499. Epub 2020 Nov 10.

Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques, UMR_S1110, F-67000 Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France; Institut Universitaire de France (IUF), Paris, France.

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http://dx.doi.org/10.1016/j.jhep.2020.10.018DOI Listing
March 2021

Liver Cirrhosis in Chronic Hepatitis B Patients Is Associated with Genetic Variations in DNA Repair Pathway Genes.

Cancers (Basel) 2020 Nov 7;12(11). Epub 2020 Nov 7.

Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland.

Liver cirrhosis (LC), contributing to more than 1 million of deaths annually, is a major healthcare concern worldwide. Hepatitis B virus (HBV) is a major LC etiological factor, and 15% of patients with chronic HBV infection (CHB) develop LC within 5 years. Recently, novel host genetic determinants were shown to influence HBV lifecycle and CHB course. DNA repair enzymes can affect dynamics of liver damage and are involved in HBV covalently closed circular DNA (cccDNA) formation, an essential step for viral replication. This study aimed to evaluate the possible role of genes representing key DNA-repair pathways in HBV-induced liver damage. MALDI-TOF MS genotyping platform was applied to evaluate variations within , , , , , , and genes. Apart from older age ( < 0.001), female sex ( = 0.021), portal hypertension ( < 0.001), thrombocytopenia ( < 0.001), high HBV DNA ( = 0.001), and high aspartate aminotransferase (AST) ( < 0.001), we found that G allele at rs238406 (, = 0.025), T allele at rs25487 (, = 0.012), rs13181 GG genotype (, = 0.034), and C allele at rs2735383 (, = 0.042) were also LC risk factors. The multivariate logistic regression model showed that rs25487 CC ( = 0.005) and rs238406 TT ( = 0.027) were independently associated with lower risk of LC. This study provides evidence for the impact of functional and potentially functional variations in key DNA-repair genes and in HBV-induced liver damage in a Caucasian population.
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http://dx.doi.org/10.3390/cancers12113295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694950PMC
November 2020

FIB-4 score and hepatocellular carcinoma risk after hepatitis C virus cure: time to revise surveillance?

Hepatobiliary Surg Nutr 2020 Oct;9(5):661-664

Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Inserm U1110, Strasbourg, France.

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http://dx.doi.org/10.21037/hbsn.2020.01.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603928PMC
October 2020

Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell.

Semin Cell Dev Biol 2021 Mar 23;111:86-100. Epub 2020 Aug 23.

Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000, Strasbourg, France. Electronic address:

As obligate intracellular parasites with limited coding capacity, RNA viruses rely on host cells to complete their multiplication cycle. Viral RNAs (vRNAs) are central to infection. They carry all the necessary information for a virus to synthesize its proteins, replicate and spread and could also play essential non-coding roles. Regardless of its origin or tropism, vRNA has by definition evolved in the presence of host RNA Binding Proteins (RBPs), which resulted in intricate and complicated interactions with these factors. While on one hand some host RBPs recognize vRNA as non-self and mobilize host antiviral defenses, vRNA must also co-opt other host RBPs to promote viral infection. Focusing on pathogenic RNA viruses, we will review important scenarios of RBP-vRNA interactions during which host RBPs recognize, modify or degrade vRNAs. We will then focus on how vRNA hijacks the largest ribonucleoprotein complex (RNP) in the cell, the ribosome, to selectively promote the synthesis of its proteins. We will finally reflect on how novel technologies are helping in deepening our understanding of vRNA-host RBPs interactions, which can be ultimately leveraged to combat everlasting viral threats.
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http://dx.doi.org/10.1016/j.semcdb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443355PMC
March 2021

Safe administration of corticosteroids in severe ulcerative colitis and active SARS-CoV2 infection.

Dig Liver Dis 2020 11 27;52(11):1257-1258. Epub 2020 Jul 27.

Department of Hepatology and Gastroenterology, Pôle Hépato-digestif, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France; Institut Hospitalo-Universitaires (IHU) de Strasbourg, Pôle Hépato-digestif, Strasbourg, France; Institut des Maladies Virales et Hépatiques, Inserm U1110, Université de Strasbourg, Faculté de Médecine, Strasbourg, France.

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http://dx.doi.org/10.1016/j.dld.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383172PMC
November 2020

Perturbation of the circadian clock and pathogenesis of NAFLD.

Metabolism 2020 10 11;111S:154337. Epub 2020 Aug 11.

Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques INSERM, UMR_S 1110, Strasbourg, France; Pôle Hépato-Digestif, Institut Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address:

All living organisms including humans, experience changes in the light exposure generated by the Earth's rotation. In anticipation of this unavoidable geo-physical variability, and to generate an appropriate biochemical response, species of many phyla, including mammals have evolved a nearly 24-hour endogenous timing device known as the circadian clock (CC), which is self-sustained, cell autonomous and is present in every cell type. At the heart of the 'clock' functioning resides the CC-oscillator, an elegantly designed transcriptional-translational feedback system. Notably, the core components of the CC-oscillator not only drive daily rhythmicity of their own synthesis, but also generate circadian phase-specific variability in the expression levels of thousands of target genes through transcriptional, post-transcriptional and post-translational mechanisms. Thereby, this 'clock'-system provides proper chronological coordination in the functioning of cells, tissues and organs. The CC governs many physiologically critical functions. Among these functions, the key role of the CC in maintaining metabolic homeostasis deserves special emphasis. Indeed, the several features of the modern lifestyle (e.g. travel-induced jet lag, rotating shift work, energy-dense food) which, force disruption of circadian rhythms have recently emerged as a major driver to global health problems like obesity, cardiovascular disease and metabolic liver disease such as non-alcoholic fatty liver disease (NAFLD). Here we review, the CC-dependent pathways in different tissues which play critical roles in mediating several critical metabolic functions under physiological conditions and discuss their impact for the development of metabolic disease with a focus on the liver.
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http://dx.doi.org/10.1016/j.metabol.2020.154337DOI Listing
October 2020

Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes.

Sci Rep 2020 07 29;10(1):12767. Epub 2020 Jul 29.

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.
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http://dx.doi.org/10.1038/s41598-020-69614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392756PMC
July 2020

Intraabdominal urokinase in the treatment of loculated infected ascites in cirrhosis.

Clin Res Hepatol Gastroenterol 2020 Jul 9:101486. Epub 2020 Jul 9.

Service de Radiologie Interventionnelle, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, France.

Cirrhotic patients may present loculated ascites. We report a case of a 49-years old patient with cirrhosis and loculated infected ascites. Conventional and ultrasound (US)-guided paracentesis were ineffective. Moreover, US-guided drainages with 10 F drains could drain only small quantities of ascites localized in the largest loculated areas. Despite an adapted and long antibiotic therapy, the infection persisted. Intraabdominal fibrinolysis allowed the destruction of the fibrin septa, a better drainage and the sterilization of the ascites fluid. This is the first case report of effective intraabdominal fibrinolysis with urokinase in difficult to treat loculated infected ascites.
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http://dx.doi.org/10.1016/j.clinre.2020.06.012DOI Listing
July 2020

Single-cell genomics and spatial transcriptomics: Discovery of novel cell states and cellular interactions in liver physiology and disease biology.

J Hepatol 2020 11 10;73(5):1219-1230. Epub 2020 Jun 10.

Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Universitaire de France, Paris, France. Electronic address:

Transcriptome analysis enables the study of gene expression in human tissues and is a valuable tool to characterise liver function and gene expression dynamics during liver disease, as well as to identify prognostic markers or signatures, and to facilitate discovery of new therapeutic targets. In contrast to whole tissue RNA sequencing analysis, single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics enables the study of transcriptional activity at the single cell or spatial level. ScRNA-seq has paved the way for the discovery of previously unknown cell types and subtypes in normal and diseased liver, facilitating the study of rare cells (such as liver progenitor cells) and the functional roles of non-parenchymal cells in chronic liver disease and cancer. By adding spatial information to scRNA-seq data, spatial transcriptomics has transformed our understanding of tissue functional organisation and cell-to-cell interactions in situ. These approaches have recently been applied to investigate liver regeneration, organisation and function of hepatocytes and non-parenchymal cells, and to profile the single cell landscape of chronic liver diseases and cancer. Herein, we review the principles and technologies behind scRNA-seq and spatial transcriptomic approaches, highlighting the recent discoveries and novel insights these methodologies have yielded in both liver physiology and disease biology.
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http://dx.doi.org/10.1016/j.jhep.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116221PMC
November 2020

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor.

Nat Commun 2020 06 1;11(1):2707. Epub 2020 Jun 1.

Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France.

Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.
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http://dx.doi.org/10.1038/s41467-020-16517-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264273PMC
June 2020

Genetic variation in IL-10 influences the progression of hepatitis B infection.

Int J Infect Dis 2020 Jul 6;96:260-265. Epub 2020 May 6.

Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland. Electronic address:

Objectives: The outcomes of hepatitis B virus (HBV) infection vary substantially among affected individuals, providing evidence of the role of host genetic background in the susceptibility to HBV persistence and the dynamics of liver injury progression to cirrhosis and hepatocellular carcinoma (HCC).

Methods: Six single-nucleotide polymorphisms within the interleukin 10 gene (IL10) were genotyped by MALDI-TOF mass spectrometry in 857 patients with chronic HBV infection (CHB), 48 patients with resolved HBV infection, and 100 healthy volunteers. Associations of the selected polymorphisms with susceptibility to chronic HBV infection, liver injury progression, and outcomes were investigated.

Results: IL10 -819T (rs1800871), -592A (rs1800872), and +504T (rs3024490) alleles were associated with treatment-induced hepatitis B surface antigen (HBsAg) seroclearance. Additionally, IL10 ATAC haplotype increased the chance of HBsAg loss and was significantly more frequent in patients with less liver injury. Moreover rs1800871TT, rs1518110TT, rs1800872AA, and rs3024490TT genotypes were identified as predictors of a lower FIB-4 score (<0.5).

Conclusions: This study indicates that polymorphisms within the promoter region and intronic sequences of IL10 are associated with chronicity of hepatitis B and with HBV-induced liver damage.
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http://dx.doi.org/10.1016/j.ijid.2020.04.079DOI Listing
July 2020

Imaging-AMARETTO: An Imaging Genomics Software Tool to Interrogate Multiomics Networks for Relevance to Radiography and Histopathology Imaging Biomarkers of Clinical Outcomes.

JCO Clin Cancer Inform 2020 05;4:421-435

Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, MA.

Purpose: The availability of increasing volumes of multiomics, imaging, and clinical data in complex diseases such as cancer opens opportunities for the formulation and development of computational imaging genomics methods that can link multiomics, imaging, and clinical data.

Methods: Here, we present the Imaging-AMARETTO algorithms and software tools to systematically interrogate regulatory networks derived from multiomics data within and across related patient studies for their relevance to radiography and histopathology imaging features predicting clinical outcomes.

Results: To demonstrate its utility, we applied Imaging-AMARETTO to integrate three patient studies of brain tumors, specifically, multiomics with radiography imaging data from The Cancer Genome Atlas (TCGA) glioblastoma multiforme (GBM) and low-grade glioma (LGG) cohorts and transcriptomics with histopathology imaging data from the Ivy Glioblastoma Atlas Project (IvyGAP) GBM cohort. Our results show that Imaging-AMARETTO recapitulates known key drivers of tumor-associated microglia and macrophage mechanisms, mediated by , , and , and neurodevelopmental and stemness mechanisms, mediated by . Imaging-AMARETTO provides interpretation of their underlying molecular mechanisms in light of imaging biomarkers of clinical outcomes and uncovers novel master drivers, and , that establish relationships across these distinct mechanisms.

Conclusion: Our network-based imaging genomics tools serve as hypothesis generators that facilitate the interrogation of known and uncovering of novel hypotheses for follow-up with experimental validation studies. We anticipate that our Imaging-AMARETTO imaging genomics tools will be useful to the community of biomedical researchers for applications to similar studies of cancer and other complex diseases with available multiomics, imaging, and clinical data.
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http://dx.doi.org/10.1200/CCI.19.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265792PMC
May 2020

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip.

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Université de Strasbourg, F-67000 Strasbourg, France.

Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.
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http://dx.doi.org/10.3390/ijms21093057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246584PMC
April 2020

Hepatitis C virus infection and tight junction proteins: The ties that bind.

Biochim Biophys Acta Biomembr 2020 07 5;1862(7):183296. Epub 2020 Apr 5.

Université de Strasbourg, INSERM, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, F-67000 Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; Institut Universitaire de France, F-75231 Paris, France. Electronic address:

The hepatitis C virus (HCV) is a major cause of liver diseases ranging from liver inflammation to advanced liver diseases like cirrhosis and hepatocellular carcinoma (HCC). HCV infection is restricted to the liver, and more specifically to hepatocytes, which represent around 80% of liver cells. The mechanism of HCV entry in human hepatocytes has been extensively investigated since the discovery of the virus 30 years ago. The entry mechanism is a multi-step process relying on several host factors including heparan sulfate proteoglycan (HSPG), low density lipoprotein receptor (LDLR), tetraspanin CD81, Scavenger Receptor class B type I (SR-BI), Epidermal Growth Factor Receptor (EGFR) and Niemann-Pick C1-like 1 (NPC1L1). Moreover, in order to establish a persistent infection, HCV entry is dependent on the presence of tight junction (TJ) proteins Claudin-1 (CLDN1) and Occludin (OCLN). In the liver, tight junction proteins play a role in architecture and homeostasis including sealing the apical pole of adjacent cells to form bile canaliculi and separating the basolateral domain drained by sinusoidal blood flow. In this review, we will highlight the role of liver tight junction proteins in HCV infection, and we will discuss the potential targeted therapeutic approaches to improve virus eradication.
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http://dx.doi.org/10.1016/j.bbamem.2020.183296DOI Listing
July 2020

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives.

Cells 2020 04 3;9(4). Epub 2020 Apr 3.

Université de Strasbourg, 67000 Strasbourg, France.

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
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http://dx.doi.org/10.3390/cells9040875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226751PMC
April 2020

Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma.

Gut 2021 Jan 26;70(1):157-169. Epub 2020 Mar 26.

Université de Strasbourg, Strasbourg, France

Objective: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.

Design: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by i and validation were used to identify chromatin modifiers and readers for HCC chemoprevention.

Results: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.

Conclusion: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.
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http://dx.doi.org/10.1136/gutjnl-2019-318918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116473PMC
January 2021

Erratum to: Repertoire and Neutralizing Activity of Antibodies Against Hepatitis C Virus E2 Peptide in Patients With Spontaneous Resolution of Hepatitis C.

J Infect Dis 2020 06;221(12):2084

Laboratory for Clinical and Experimental Hepatology, Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1093/infdis/jiaa052DOI Listing
June 2020

Characterisation of endogenous Claudin-1 expression, motility and susceptibility to hepatitis C virus in CRISPR knock-in cells.

Biol Cell 2020 May 20;112(5):140-151. Epub 2020 Feb 20.

CNRS, IRIM Institut de Recherche en infectiologie de Montpellier, Montpellier, 34293, France.

Background Information: Claudin-1 (CLDN1) is a four-span transmembrane protein localised at cell-cell tight junctions (TJs), playing an important role in epithelial impermeability and tissue homoeostasis under physiological conditions. Moreover, CLDN1 expression is up-regulated in several cancers, and the level of CLDN1 expression has been proposed as a prognostic marker of patient survival.

Results: Here, we generated and characterised a novel reporter cell line expressing endogenous fluorescent levels of CLDN-1, allowing dynamic monitoring of CLDN-1 expression levels. Specifically, a hepatocellular carcinoma Huh7.5.1 monoclonal cell line was bioengineered using CRISPR/Cas9 to endogenously express a fluorescent TagRFP-T protein fused at the N-terminus of the CLDN1 protein. These cells were proved useful to measure CLDN1 expression and distribution in live cells. However, the cells were resistant to hepatitis C virus (HCV) infection, of which CLDN1 is a viral receptor, while retaining permissiveness to VSV-G-decorated pseudoparticles. Nonetheless, the TagRFP-CLDN1 cell line showed expected CLDN1 protein localisation at TJs and the cell monolayer had similar impermeability and polarisation features as its wild-type counterpart. Finally, using fluorescence recovery after photobleaching (FRAP) approaches, we measured that the majority of endogenous and overexpressed TagRFP-CLDN1 diffuses rapidly within the TJ, whereas half of the overexpressed EGFP-CLDN1 proteins were stalled at TJs.

Conclusions: The Huh7.5.1 TagRFP-CLDN1 edited cell line showed physiological features comparable to that of non-edited cells, but became resistant to HCV infection. Our data also highlight the important impact of the fluorescent protein chosen for endogenous tagging.

Significance: Although HCV-related studies may not be achieved with these cells, our work provides a novel tool to study the cell biology of TJ-associated proteins and a potential screening strategy measuring CLDN1 expression levels.
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http://dx.doi.org/10.1111/boc.201900085DOI Listing
May 2020

Tight Junction Proteins and the Biology of Hepatobiliary Disease.

Int J Mol Sci 2020 Jan 28;21(3). Epub 2020 Jan 28.

Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm UMR1110, F-67000 Strasbourg, France.

Tight junctions (TJ) are intercellular adhesion complexes on epithelial cells and composed of integral membrane proteins as well as cytosolic adaptor proteins. Tight junction proteins have been recognized to play a key role in health and disease. In the liver, TJ proteins have several functions: they contribute as gatekeepers for paracellular diffusion between adherent hepatocytes or cholangiocytes to shape the blood-biliary barrier (BBIB) and maintain tissue homeostasis. At non-junctional localizations, TJ proteins are involved in key regulatory cell functions such as differentiation, proliferation, and migration by recruiting signaling proteins in response to extracellular stimuli. Moreover, TJ proteins are hepatocyte entry factors for the hepatitis C virus (HCV)-a major cause of liver disease and cancer worldwide. Perturbation of TJ protein expression has been reported in chronic HCV infection, cholestatic liver diseases as well as hepatobiliary carcinoma. Here we review the physiological function of TJ proteins in the liver and their implications in hepatobiliary diseases.
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http://dx.doi.org/10.3390/ijms21030825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038100PMC
January 2020

Targeting the Host for New Therapeutic Perspectives in Hepatitis D.

J Clin Med 2020 Jan 14;9(1). Epub 2020 Jan 14.

Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000 Strasbourg, France.

Hepatitis D virus (HDV) is a small satellite virus of hepatitis B virus (HBV) requiring HBV infection to complete its life cycle. It has been recently estimated that 13% of chronic HBV infected patients (60 million) are co-infected with HDV. Chronic hepatitis D is the most severe form of viral hepatitis with the highest risk to develop cirrhosis and liver cancer. Current treatment is based on pegylated-interferon-alpha which rarely controls HDV infection and is complicated by serious side effects. The development of novel antiviral strategies based on host targeting agents has shown promising results in phase I/II clinical trials. This review summarizes HDV molecular virology and physiopathology as well as new therapeutic approaches targeting HDV host factors.
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http://dx.doi.org/10.3390/jcm9010222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019876PMC
January 2020