Thomas F Baumert

Institut de Recherche contre les Cancers de l'Appareil Digestif, Strasburg, Alsace, France

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Publications (230)1771.53 Total impact

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    Che C. Colpitts, Eloi R. Verrier, Thomas F. Baumert
    05/2015; DOI:10.1021/acsinfecdis.5b00039
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    ABSTRACT: Since their discovery, tremendous progress has been made in our understanding of the roles of claudins in tight junction physiology. In addition, interactions between claudins and other cellular proteins have highlighted their novel roles in cell physiology. Moreover, the importance of claudins is becoming apparent in the pathophysiology of several diseases, including viral infections. Notable is the discovery of CLDN1 as an essential host factor for hepatitis C virus (HCV) entry, which led to detailed characterization of CLDN1 and its association with tetraspanin CD81 for the initiation of HCV infection. CLDN1 has also been shown to facilitate dengue virus entry. Furthermore, owing to the roles of claudins in forming anatomical barriers, several viruses have been shown to alter claudin expression at the tight junction. This review summarizes the role of claudins in viral infection, with particular emphasis on HCV. Copyright © 2015. Published by Elsevier Ltd.
    Seminars in Cell and Developmental Biology 05/2015; DOI:10.1016/j.semcdb.2015.04.011 · 5.97 Impact Factor
  • Che C Colpitts, Mirjam B Zeisel, Thomas F Baumert
    Hepatology 04/2015; DOI:10.1002/hep.27876 · 11.19 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infection relies on virus-host interactions with human hepatocytes, a context in which host cell kinases play critical roles in every step of the HCV life cycle. During viral entry, cellular kinases, including EGFR, EphA2 and PKA, regulate the localization of host HCV entry factors and induce receptor complex assembly. Following virion internalization, viral genomes replicate on endoplasmic reticulum-derived membranous webs. The formation of membranous webs depends on interactions between the HCV NS5a protein and PI4KIIIα. The phosphorylation status of NS5a, regulated by PI4KIIIα, CKI and other kinases, also acts as a molecular switch to virion assembly, which takes place on lipid droplets. The formation of lipid droplets is enhanced by HCV activation of IKKα. In view of the multiple crucial steps in the viral life cycle that are mediated by host cell kinases, these enzymes also represent complementary targets for antiviral therapy. This article is part of a Special Issue entitled:Inhibitors of Protein Kinases. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; DOI:10.1016/j.bbapap.2015.04.011 · 4.66 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.
    Nature Biotechnology 03/2015; 33(5). DOI:10.1038/nbt.3179 · 39.08 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir. We screened cholangiocytes along with a panel of cholangiocarcinoma-derived cell lines for their ability to support HCV entry and replication. While primary cholangiocytes were refractory to infection and lacked expression of several entry factors, two cholangiocarcinoma lines, CC-LP-1 and Sk-ChA-1, supported efficient HCV entry; furthermore, Sk-ChA-1 cells supported full virus replication. In vivo cholangiocarcinomas expressed all of the essential HCV entry factors; however, cholangiocytes adjacent to the tumor and in normal tissue showed a similar pattern of receptor expression to ex vivo isolated cholangiocytes, lacking SR-BI expression, explaining their inability to support infection. This study provides the first report that HCV can infect cholangiocarcinoma cells and suggests that these heterogeneous tumors may provide a reservoir for HCV replication in vivo.
    Journal of General Virology 02/2015; DOI:10.1099/vir.0.000090 · 3.53 Impact Factor
  • Journal of the American College of Surgeons 01/2015; 220(5). DOI:10.1016/j.jamcollsurg.2014.12.053 · 4.45 Impact Factor
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31-6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0-1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96-3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13-7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression.
    PLoS ONE 12/2014; 9(12):e114747. DOI:10.1371/journal.pone.0114747 · 3.53 Impact Factor
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    ABSTRACT: Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is associated with accelerated progression of liver disease, frequently leading to graft loss and early death. Existing treatment options for severe recurrent HCV infection are limited by suboptimal efficacy, poor tolerability, and numerous drug interactions. We provided sofosbuvir and ribavirin on a compassionate-use basis to patients with severe recurrent hepatitis C, including those with fibrosing cholestatic hepatitis (FCH) and decompensated cirrhosis who had a life expectancy of one year or less. All patients were to receive 24-48 weeks of sofosbuvir plus ribavirin. Investigators could add peginterferon to the regimen at their discretion. Data from the first 104 patients who completed or prematurely discontinued treatment by January 1, 2014 are presented. Of the 104 patients analyzed, 52 had an early severe recurrence (diagnosed <12 months after LT) and 52 had cirrhosis (diagnosed >12 months after LT). Twelve patients who underwent retransplantation were excluded from our efficacy analysis. Of the 92 patients assessed, 54 (59%) achieved sustained virologic response at 12 weeks after the end of treatment (SVR12), with a higher rate (73%, 35/48) in patients with early severe recurrence. Of the 103 patients assessed for clinical outcome, 59 (57%) reported clinical improvement at the last study visit, 23 (22%) were unchanged, three (3%) had a worsened clinical status, and 13 (13%) died. Overall, 123 serious adverse events (SAEs) occurred in 49 patients (47%). SAEs associated with hepatic decompensation were the most frequent, with 26 SAEs occurring in 19 patients (18%). Conclusion: Sofosbuvir and ribavirin provide high rates of sustained virologic response in patients with severe recurrent HCV, including patients with early severe recurrence, FCH, and cirrhosis. This article is protected by copyright. All rights reserved.
    Hepatology 12/2014; 61(5). DOI:10.1002/hep.27681 · 11.19 Impact Factor
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    Hepatology 12/2014; 60(6). DOI:10.1002/hep.27326 · 11.19 Impact Factor
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    ABSTRACT: Fighting viral infections is hampered by the scarcity of viral targets and their variability, resulting in devel-opment of resistance. Viruses depend on cellular molecules—which are attractive alternative tar-gets—for their life cycle, provided that they are dispensable for normal cell functions. Using the model organism Drosophila melanogaster, we iden-tify the ribosomal protein RACK1 as a cellular factor required for infection by internal ribosome entry site (IRES)-containing viruses. We further show that RACK1 is an essential determinant for hepatitis C virus translation and infection, indicating that its function is conserved for distantly related human and fly viruses. Inhibition of RACK1 does not affect Drosophila or human cell viability and proliferation, and RACK1-silenced adult flies are viable, indicating that this protein is not essential for general transla-tion. Our findings demonstrate a specific function for RACK1 in selective mRNA translation and un-cover a target for the development of broad antiviral intervention. INTRODUCTION
    Cell 11/2014; 159(5):1086 - 1095. DOI:10.13140/2.1.1887.7123 · 33.12 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV)-induced, end-stage liver disease is a major indication for liver transplantation, but systematic graft reinfection accelerates liver disease recurrence. Transplantation recipients may be ineligible for direct-acting antivirals, owing to toxicity, resistance or advanced liver disease. Adoptive immunotherapy with liver graft-derived, ex vivo-activated lymphocytes was previously shown to prevent HCV-induced graft reinfections. Alternatively, the applicability and therapeutic efficacy of adoptive immunotherapy may be enhanced by 'ready for use' suicide gene-modified lymphocytes from healthy blood donors; moreover, conditional, prodrug-induced cell suicide may prevent potential side effects. Here, we demonstrate that allogeneic suicide gene-modified lymphocytes (SGMLs) could potently, dose- and time-dependently, inhibit viral replication. The effect occurs at effector:target cell ratios that exhibits no concomitant cytotoxicity toward virus-infected target cells. The effect, mediated mostly by CD56+ lymphocytes, is interleukin-2-dependent, IFN-γ-mediated and, importantly, resistant to calcineurin inhibitors. Thus, post-transplant immunosuppression may not interfere with this adoptive cell immunotherapy approach. Furthermore, these cells are indeed amenable to conditional cell suicide; in particular, the inducible caspase 9 suicide gene is superior to the herpes simplex virus thymidine kinase suicide gene. Our data provide in vitro proof-of-concept that allogeneic, third-party, SGMLs may prevent HCV-induced liver graft reinfection.Gene Therapy advance online publication, 13 November 2014; doi:10.1038/gt.2014.99.
    Gene Therapy 11/2014; 22(2). DOI:10.1038/gt.2014.99 · 4.20 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.07.010 · 10.40 Impact Factor
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    Thomas F. Baumert, Stefan Zeuzem
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.08.034 · 10.40 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus–host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.09.009 · 10.40 Impact Factor
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    ABSTRACT: Being the largest internal organ of the human body with the unique ability of self-regeneration, the liver is involved in a wide variety of vital functions that require highly orchestrated and controlled biochemical processes. Increasing evidence suggests that microRNA (miRNA) are essential for the regulation of liver development, regeneration and metabolic functions. Hence, alterations in intrahepatic miRNA networks have been associated with liver disease including hepatitis, steatosis, cirrhosis and hepatocellular carcinoma (HCC). miR-122 is the most frequent miRNA in the adult liver, and a central player in liver biology and disease. Furthermore, miR-122 has been shown to be an essential host factor for hepatitis C virus (HCV) infection and an antiviral target complementary to standard of care using direct-acting antivirals or interferon-based treatment. This review summarizes our current understanding of the key role of miR-122 in liver physiology and disease highlighting its role in HCC and viral hepatitis. We also discuss the perspectives of miRNA-based therapeutic approaches for viral hepatitis and liver disease.
    Journal of Hepatology 10/2014; 62(2). DOI:10.1016/j.jhep.2014.10.004 · 10.40 Impact Factor
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    ABSTRACT: Introduction Une embolisation portale (EP) seule ou associée de manière séquentielle avec une chimioembolisation intra-artérielle (CEIA) a été proposée avant une résection hépatique pour carcinome hépato-cellulaire (CHC). Le but de cette étude était de comparer les suites opératoires précoces de ces deux stratégies. Méthodes De janvier 2012 à juin 2013, 12 patients atteints de CHC recevaient un traitement séquentiel CEIA + EP (groupe 1, G1). Le groupe-contrôle (12 patients) était traité par EP seule avant chirurgie (groupe 2, G2). Résultats Les caractéristiques des patients et des tumeurs étaient identiques dans les deux groupes. L’augmentation moyenne de VFR était de 7,36 % dans le G1 et 4,6 % dans le G2 (p = ns). Dans le G1, 10 hépatectomies majeures ont été réalisées vs 12 dans le G2 (p = ns). L’incidence d’insuffisance hépato-cellulaire (IHC) post-opé-ratoire était plus élevée dans le G2 (41,6 %, 5/12) que dans le G1 (8,3 %, 1/12). Parmi les 5 patients du G2, seul un est décédé d’IHC post-opératoire. Les taux de complications et de mortalité postopératoire n’étaient pas différents dans les 2 groupes. La durée de séjour en réanimation était plus élevée dans le G1 que dans le G2 (p = 0,03). L’incidence de nécrose tumorale était significativement plus élevée dans le G1 (11/12 vs 3/12 p = 0,002). Conclusion Le traitement séquentiel CEIA + EP avant hépa-tectomie pour CHC augmente le volume de foie restant, avec des suites opératoire plus simples, et augmente le taux de nécrose tumorale.
    10/2014; 151(4):A5–A6. DOI:10.1016/S1878-786X(14)70097-X
  • Rajiv G Tawar, Laurent Mailly, Thomas F Baumert
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    ABSTRACT: The investigation of virus-induced liver disease and hepatocellular carcinoma needs small animal models modeling hepatitis C virus (HCV) infection and liver disease biology. A recent study published in Cell Research reports a novel mouse model which is permissive for chronic HCV infection and shows chronic liver injury including inflammation, steatosis and fibrosis.
    Cell Research 09/2014; 24(10). DOI:10.1038/cr.2014.126 · 11.98 Impact Factor
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    Eloi R. Verrier, Michaela U. Gack, Thomas F. Baumert
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    ABSTRACT: The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single stranded RNA viruses more effectively than negative-sense single stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families. (Hepatology 2014;)
    Hepatology 09/2014; 60(3). DOI:10.1002/hep.27187 · 11.19 Impact Factor

Publication Stats

5k Citations
1,771.53 Total Impact Points


  • 2015
    • Institut de Recherche contre les Cancers de l'Appareil Digestif
      Strasburg, Alsace, France
  • 2007–2015
    • University of Strasbourg
      • Laboratoire de BioVectorologie
      Strasburg, Alsace, France
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2008–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1998–2014
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2013
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
    • Imperial College London
      Londinium, England, United Kingdom
  • 2012
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2010–2012
    • University of Birmingham
      • • School of Biosciences
      • • Institute for Biomedical Research
      Birmingham, England, United Kingdom
    • Stanford University
      • Department of Pathology
      Palo Alto, California, United States
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      • Department of Biology and Stem Cell Development
      Strasburg, Alsace, France
  • 2011
    • Cancer Research Center of Lyon
      Lyons, Rhône-Alpes, France
  • 2008–2011
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2001–2009
    • University of Freiburg
      • • Faculty of Biology
      • • Department of Internal Medicine
      Freiburg, Baden-Württemberg, Germany
  • 2006–2007
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • Rensselaer Polytechnic Institute
      • Department of Chemical and Biological Engineering
      Troy, New York, United States
  • 2004
    • Technische Universität München
      München, Bavaria, Germany
  • 1996–2001
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Maryland, United States
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, MA, United States