29 results on '"Faure-Dupuy S"'
Search Results
2. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control
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Namineni, S, additional, O'Connor, T, additional, Faure-Dupuy, S, additional, Johansen, P, additional, Riedl, T, additional, Liu, K, additional, Xu, H, additional, Singh, I, additional, Shinde, P, additional, Li, F, additional, Pandyra, A, additional, Sharma, P, additional, Ringelhan, M, additional, Muschaweckh, A, additional, Borst, K, additional, Blank, P, additional, Lampl, S, additional, Durantel, D, additional, Farhat, R, additional, Weber, A, additional, Lenggenhager, D, additional, Kündig, TM, additional, Stäheli, P, additional, Protzer, U, additional, Wohlleber, D, additional, Holzmann, B, additional, Binder, M, additional, Breuhahn, K, additional, Abdullah, Z, additional, Rolland, M, additional, Dejardin, E, additional, Lang, PA, additional, Lang, KS, additional, Karin, M, additional, Lucifora, J, additional, Kalinke, U, additional, Knolle, PA, additional, and Heikenwalder, M, additional
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- 2020
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3. Early function modulation and reprogramming of Kupffer cells promote establishment and maintenance of HBV infection
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Faure-Dupuy, S., primary, Aillot, L., additional, Isorce, N., additional, Dimier, L., additional, Testoni, B., additional, Lam, A., additional, Klumpp, K., additional, Zanetti, C., additional, Bendriss-Vermare, N., additional, Hasan, U., additional, Zoulim, F., additional, Lucifora, J., additional, and Durantel, D., additional
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- 2017
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4. SAT-185 - Early function modulation and reprogramming of Kupffer cells promote establishment and maintenance of HBV infection
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Faure-Dupuy, S., Aillot, L., Isorce, N., Dimier, L., Testoni, B., Lam, A., Klumpp, K., Zanetti, C., Bendriss-Vermare, N., Hasan, U., Zoulim, F., Lucifora, J., and Durantel, D.
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- 2017
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5. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
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Arun J. Sanyal, Claudia P. Oliveira, Andrew V. Uzilov, Beatriz Minguez, Huan Wang, Suzanne Faure-Dupuy, Sara Torrecilla, Helen L. Reeves, Jean-François Dufour, Mathias Heikenwalder, Carmen Andreu-Oller, Flair José Carrilho, Charissa Chang, Catherine E. Willoughby, Marta Piqué-Gili, Scott L. Friedman, Leow Wei-Qiang, Svenja Schuehle, Judit Peix, Carla Montironi, Paolo Boffetta, Josep M. Llovet, Stephanie Roessler, Roser Pinyol, Peter Schirmacher, Miguel Torres-Martin, Patricia Taik, Venancio Avancini Ferreira Alves, Youngmin A. Lee, Tobias Riedl, Pierluigi Ramadori, Daniela Sia, Agrin Moeini, Anja Lachenmayer, Swan N. Thung, Pinyol R., Torrecilla S., Wang H., Montironi C., Pique-Gili M., Torres-Martin M., Wei-Qiang L., Willoughby C.E., Ramadori P., Andreu-Oller C., Taik P., Lee Y.A., Moeini A., Peix J., Faure-Dupuy S., Riedl T., Schuehle S., Oliveira C.P., Alves V.A., Boffetta P., Lachenmayer A., Roessler S., Minguez B., Schirmacher P., Dufour J.-F., Thung S.N., Reeves H.L., Carrilho F.J., Chang C., Uzilov A.V., Heikenwalder M., Sanyal A., Friedman S.L., Sia D., and Llovet J.M.
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0301 basic medicine ,Male ,obesity ,Síndrome metabòlica ,Subclass ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Molecular models ,Exome sequencing ,Aged, 80 and over ,Liver Neoplasms ,Animal models in research ,mutational signature ,Middle Aged ,Metabolic syndrome ,Liver Neoplasm ,Hepatocellular carcinoma ,Obesitat ,030211 gastroenterology & hepatology ,Female ,Liver cancer ,Human ,Carcinoma, Hepatocellular ,Biology ,digestive system ,metabolic syndrome ,Models moleculars ,liver cancer ,Càncer de fetge ,03 medical and health sciences ,medicine ,Humans ,Obesity ,molecular cla ,neoplasms ,Molecular Biology ,Aged ,Hepatology ,animal model ,Mutació (Biologia) ,Cancer ,nutritional and metabolic diseases ,HCCS ,Mutation (Biology) ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Cancer research ,Steatohepatitis ,Models animals en la investigació ,610 Medizin und Gesundheit ,ACVR2A - Abstract
BACKGROUND AND AIMS Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p
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- 2020
6. Human rhinovirus 16 induces an ICAM-1-PKR-ATF2 axis to modulate macrophage functions.
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Faure-Dupuy S, Depierre M, Fremont-Debaene Z, Herit F, and Niedergang F
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- Humans, Picornaviridae Infections metabolism, Picornaviridae Infections virology, Picornaviridae Infections genetics, Promoter Regions, Genetic, Epigenesis, Genetic, Intercellular Adhesion Molecule-1 metabolism, Intercellular Adhesion Molecule-1 genetics, Macrophages virology, Macrophages metabolism, Rhinovirus physiology, Activating Transcription Factor 2 metabolism, Activating Transcription Factor 2 genetics, Signal Transduction
- Abstract
Human rhinovirus (HRV) infections are the leading cause of disease exacerbations in individuals with chronic pulmonary diseases, primarily due to impaired macrophage functions, resulting in defective bacterial elimination. We previously demonstrated that HRV16 impairs macrophages' functions in an ARL5b-dependent manner. In permissive cells, ARL5b acted as an HRV16 restriction factor and was repressed. Here, we delve into the dual regulation of ARL5b by HRV16 in both cell types. We analyzed the effect of HRV16 on primary human macrophages using neutralizing antibodies, specific inhibitors, siRNA, and chromatin immune precipitation. Our study reveals that, while the virus does not replicate in macrophages, it induces interferon and pro-inflammatory responses. We identify the ICAM-1-PKR-ATF2 signaling axis as crucial for ARL5b induction in macrophages, whereas only ICAM-1 plays a role in ARL5b repression in permissive cells. Furthermore, HRV16 triggers epigenetic reprogramming in both cell types at the ARL5b promoter. In macrophages, epigenetic changes are ATF2 dependent. In conclusion, our findings highlight previously unknown signaling pathways activated by HRV16 in macrophages. Targeting these pathways could offer novel strategies to improve outcomes for individuals with respiratory conditions., Importance: Human rhinovirus (HRV) infections are the leading cause of disease exacerbations in individuals with chronic pulmonary conditions and are frequently associated with bacterial superinfections due to defective bacterial elimination by macrophages. We previously identified ARL5b-induction by HRV16 to be responsible for the impairment of bacteria elimination. In contrast, in permissive cells, ARL5b is repressed and acts as a restriction factor for HRV16. Here, we investigated the dual regulation of ARL5b by HRV16 in these cells. Our study reveals that the ICAM-1-PKR-ATF2 signaling axis is crucial for ARL5b induction in macrophages. In permissive cells, only ICAM-1 plays a role in ARL5b repression. Moreover, HRV16 triggered epigenetic reprogramming in macrophages. ARL5b promoter was repressed in an ATF2-dependent manner. Collectively, our findings reveal previously unknown signaling pathways activated by HRV16 in macrophages. Targeting these pathways provides novel strategies to target ARL5b expression specifically in macrophages and improve outcomes for individuals with respiratory pathologies., Competing Interests: M.D., Z.F.-D., and F.H. declare no conflict of interest. S.F.-D. and F.N. are the inventors of patent no. EP24306042.3.
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- 2024
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7. Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells.
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Tran CS, Kersten J, Yan J, Breinig M, Huth T, Poth T, Colasanti O, Riedl T, Faure-Dupuy S, Diehl S, Verhoye L, Li TF, Lingemann M, Schult P, Ahlén G, Frelin L, Kühnel F, Vondran FWR, Breuhahn K, Meuleman P, Heikenwälder M, Schirmacher P, Bartenschlager R, Laketa V, Roessler S, Tschaharganeh DF, Sällberg M, and Lohmann V
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- Humans, Animals, Mice, Phosphorylation, Hepacivirus, Cell Line, Tumor, Phosphotransferases (Alcohol Group Acceptor) metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Hep G2 Cells, Hepatitis C pathology, Hepatitis C metabolism, Hepatitis C virology, RNA Interference, Liver Neoplasms pathology, Liver Neoplasms metabolism, Liver Neoplasms genetics, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular genetics, Cytoskeleton metabolism, Cytoskeleton pathology, Neoplasm Invasiveness, Paxillin metabolism, Signal Transduction, Cell Movement, Actin Depolymerizing Factors metabolism, Actin Depolymerizing Factors genetics
- Abstract
Background & Aims: High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process., Methods: Several hepatic cell culture and mouse models were used to study the functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing, and PI4KIIIα-specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein., Results: High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased phosphorylation of paxillin and cofilin. This led to morphologic alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver-specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that regulate cytoskeletal reorganization by promoting Akt2 phosphorylation., Conclusions: PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to the progression of liver cancer and identify promising targets for therapeutic intervention., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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8. HBV-related HCC development in mice is STAT3 dependent and indicates an oncogenic effect of HBx.
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Ringelhan M, Schuehle S, van de Klundert M, Kotsiliti E, Plissonnier ML, Faure-Dupuy S, Riedl T, Lange S, Wisskirchen K, Thiele F, Cheng CC, Yuan D, Leone V, Schmidt R, Hünergard J, Geisler F, Unger K, Algül H, Schmid RM, Rad R, Wedemeyer H, Levrero M, Protzer U, and Heikenwalder M
- Abstract
Background & Aims: Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice., Methods: HBV-transgenic mice replicating HBV and expressing all HBV proteins from a single integrated 1.3-fold HBV genome in the presence or absence of wild-type HBx (HBV1.3/HBVxfs) were analyzed. Flow cytometry, molecular, histological and in vitro analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice., Results: Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development., Conclusions: Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV 'cure'., Impact and Implications: Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the 'immune-tolerant' phase (HBeAg-positive chronic HBV infection)., (© 2024 The Authors.)
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- 2024
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9. [HRV16 inhibits bacterial clearance in a ARL5b-dependent manner].
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Fremont-Debaene Z and Faure-Dupuy S
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- Humans, Animals, ADP-Ribosylation Factor 6, Mice, ADP-Ribosylation Factors metabolism, ADP-Ribosylation Factors physiology, ADP-Ribosylation Factors genetics
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- 2024
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10. ARL5b inhibits human rhinovirus 16 propagation and impairs macrophage-mediated bacterial clearance.
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Faure-Dupuy S, Jubrail J, Depierre M, Africano-Gomez K, Öberg L, Israelsson E, Thörn K, Delevoye C, Castellano F, Herit F, Guilbert T, Russell DG, Mayer G, Cunoosamy DM, Kurian N, and Niedergang F
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- Humans, Macrophages, Alveolar, Phagocytosis, Bacteria, Rhinovirus, Macrophages microbiology
- Abstract
Human rhinovirus is the most frequently isolated virus during severe exacerbations of chronic respiratory diseases, like chronic obstructive pulmonary disease. In this disease, alveolar macrophages display significantly diminished phagocytic functions that could be associated with bacterial superinfections. However, how human rhinovirus affects the functions of macrophages is largely unknown. Macrophages treated with HRV16 demonstrate deficient bacteria-killing activity, impaired phagolysosome biogenesis, and altered intracellular compartments. Using RNA sequencing, we identify the small GTPase ARL5b to be upregulated by the virus in primary human macrophages. Importantly, depletion of ARL5b rescues bacterial clearance and localization of endosomal markers in macrophages upon HRV16 exposure. In permissive cells, depletion of ARL5b increases the secretion of HRV16 virions. Thus, we identify ARL5b as a novel regulator of intracellular trafficking dynamics and phagolysosomal biogenesis in macrophages and as a restriction factor of HRV16 in permissive cells., (© 2024. The Author(s).)
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- 2024
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11. Corrigendum to "Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation" [J Hepatol (2023) 645-656].
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Colasanti O, Burm R, Huang HE, Riedl T, Traut J, Gillich N, Li TF, Corneillie L, Faure-Dupuy S, Grünvogel O, Heide D, Lee JY, Tran CS, Merle U, Chironna M, Vondran FFW, Esser-Nobis K, Binder M, Bartenschlager R, Heikenwälder M, Meuleman P, and Lohmann V
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- 2024
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12. Targeting immuno-metabolism and anti-viral immune responses in chronic hepatitis B.
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Faure-Dupuy S and Baumert TF
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- Humans, Hepatitis B Surface Antigens, Immunity, Hepatitis B virus, Hepatitis B, Chronic drug therapy, Hepatitis B
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- 2023
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13. Virus hijacking of host epigenetic machinery to impair immune response.
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Locatelli M and Faure-Dupuy S
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- Humans, DNA Methylation, Immunity, Host-Pathogen Interactions, Epigenesis, Genetic, Virus Diseases genetics, Virus Diseases immunology, Viruses genetics
- Abstract
Epigenetic modifications, such as DNA hypermethylation, histone acetylation/methylation, or nucleosome positioning, result in differential gene expression. These modifications can have an impact on various pathways, including host antiviral immune responses. In this review, we summarize the current understanding of epigenetic modifications induced by viruses to counteract host antiviral immune responses, which are crucial for establishing and maintaining infection of viruses. Finally, we provide insights into the potential use of epigenetic modulators in combating viral infections and virus-induced diseases., Competing Interests: The authors declare no conflict of interest.
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- 2023
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14. Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation.
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Colasanti O, Burm R, Huang HE, Riedl T, Traut J, Gillich N, Li TF, Corneillie L, Faure-Dupuy S, Grünvogel O, Heide D, Lee JY, Tran CS, Merle U, Chironna M, Vondran FFW, Esser-Nobis K, Binder M, Bartenschlager R, Heikenwälder M, Meuleman P, and Lohmann V
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- Hepatitis A virus, Hepacivirus, Animals, Mice, Mice, SCID, Hepatitis A, Hepatitis C, Immune Evasion, Immunity, Innate
- Abstract
Background & Aims: Hepatitis A virus (HAV) infections are considered not to trigger innate immunity in vivo, in contrast to hepatitis C virus (HCV). This lack of induction has been imputed to strong interference by HAV proteases 3CD and 3ABC. We aimed to elucidate the mechanisms of immune activation and counteraction by HAV and HCV in vivo and in vitro., Methods: Albumin-urokinase-type plasminogen activator/severe combined immunodeficiency (Alb/uPA-SCID) mice with humanised livers were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by Toll-like receptor 3 and retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5), respectively. Cleavage of the adaptor proteins TIR-domain-containing adapter-inducing interferon-β (TRIF) and mitochondrial antiviral-signalling protein (MAVS) was analysed by transient and stable expression of HAV and HCV proteases and virus infection., Results: We detected similar levels of interferon-stimulated gene induction in hepatocytes of HAV- and HCV-infected mice with humanised liver. In cell culture, HAV induced interferon-stimulated genes exclusively upon MDA5 sensing and depended on LGP2 (laboratory of genetics and physiology 2). TRIF and MAVS were only partially cleaved by HAV 3ABC and 3CD, not sufficiently to abrogate signalling. In contrast, HCV NS3-4A efficiently degraded MAVS, as previously reported, whereas TRIF cleavage was not detected., Conclusions: HAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates Toll-like receptor 3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV-induced antiviral responses in hepatocytes. Our results shed new light on the induction of innate immunity and counteraction by HAV and HCV., Impact and Implications: Understanding the mechanisms that determine the differential outcomes of HAV and HCV infections is crucial for the development of effective therapies. Our study provides insights into the interplay between these viruses and the host innate immune response in vitro and in vivo, shedding light on previously controversial or only partially investigated aspects. This knowledge could tailor the development of new strategies to combat HCV persistence, as well as improve our understanding of the factors underlying successful HAV clearance., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2023
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15. Inhibitory Effect of IL-1β on HBV and HDV Replication and HBs Antigen-Dependent Modulation of Its Secretion by Macrophages.
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Delphin M, Faure-Dupuy S, Isorce N, Rivoire M, Salvetti A, Durantel D, and Lucifora J
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- Antiviral Agents pharmacology, Coinfection, Cytokines, Hepatitis B virology, Hepatitis B virus genetics, Hepatitis Delta Virus genetics, Hepatocytes, Humans, Immunity, Innate, RNA, Small Interfering, Hepatitis B Surface Antigens immunology, Hepatitis B virus drug effects, Hepatitis Delta Virus drug effects, Interleukin-1beta antagonists & inhibitors, Macrophages immunology, Virus Replication drug effects
- Abstract
Co-infection with the hepatitis B virus and hepatitis delta virus (HDV) leads to the most aggressive form of viral hepatitis. Using in vitro infection models, we confirmed that IL-1β, a crucial innate immune molecule for pathogen control, was very potent against HBV from different genotypes. Additionally, we demonstrated for the first time a strong and rapid antiviral effect induced by very low doses of IL-1β against HDV. In parallel, using co-culture assays, we demonstrated that monocytes exposed to HBV, and in particular to HBsAg, during differentiation into pro-inflammatory macrophages secreted less IL-1β. Altogether, our data emphasize the importance of developing combined antiviral strategies that would, for instance, reduce the secretion of HBsAg and stimulate the immune system to produce endogenous IL-1β efficient against both HBV and HDV.
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- 2021
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16. Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro .
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Michelet M, Alfaiate D, Chardès B, Pons C, Faure-Dupuy S, Engleitner T, Farhat R, Riedl T, Legrand AF, Rad R, Rivoire M, Zoulim F, Heikenwälder M, Salvetti A, Durantel D, and Lucifora J
- Abstract
Background & Aims: HDV superinfection of chronically HBV-infected patients is the most aggressive form of chronic viral hepatitis, with an accelerated progression towards fibrosis/cirrhosis and increased risk of liver failure, hepatocellular carcinoma, and death. While HDV infection is not susceptible to available direct anti-HBV drugs, suboptimal responses are obtained with interferon-α-based therapies, and the number of investigational drugs remains limited. We therefore analyzed the effect of several innate immune stimulators on HDV replication in infected hepatocytes., Methods: We used in vitro models of HDV and HBV infection based on primary human hepatocytes (PHHs) and the non-transformed HepaRG cell line that are relevant to explore new innate immune therapies., Results: We describe here, for the first time, anti-HDV effects of Pam3CSK4 and BS1, agonists of Toll-like receptor (TLR)-1/2, and the lymphotoxin-β receptor (LTβR), respectively. Both types of agonists induced dose-dependent reductions of total intracellular HDV genome and antigenome RNA and of HDV protein levels, without toxicity in cells monoinfected with HDV or co/superinfected with HBV. Moreover, both molecules negatively affected HDV progeny release and strongly decreased their specific infectivity. The latter effect is particularly important since HDV is thought to persist in humans through constant propagation., Conclusions: Immune-modulators inducing NF-κB pathways in hepatocytes can inhibit HDV replication and should be further evaluated as a possible therapeutic approach in chronically HBV/HDV-infected patients., Lay Summary: Hepatitis delta virus causes the most severe form of viral hepatitis. Despite positive recent developments, effective treatments remain a major clinical need. Herein, we show that immune-modulators that trigger the NF-κB pathways could be effective for the treatment of hepatitis delta infections., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)
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- 2021
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17. Corrigendum to 'Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis' [J Hepatol 75 (2021) 865-878].
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Pinyol R, Torrecilla S, Wang H, Montironi C, Piqué-Gili M, Torres-Martin M, Wei-Qiang L, Willoughby CE, Ramadori P, Andreu-Oller C, Taik P, Lee YA, Moeini A, Peix J, Faure-Dupuy S, Riedl T, Schuehle S, Oliveira CP, Alves VA, Boffetta P, Lachenmayer A, Roessler S, Minguez B, Schirmacher P, Dufour JF, Thung SN, Reeves HL, Carrilho FJ, Chang C, Uzilov AV, Heikenwalder M, Sanyal A, Friedman SL, Sia D, and Llovet JM
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- 2021
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18. How to get away with liver innate immunity? A viruses' tale.
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, and Faure-Dupuy S
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- Interferons, Liver, Receptors, Pattern Recognition, Immunity, Innate, Viruses
- Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype)., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)
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- 2021
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19. Hypoxia-Inducible Factor 1 Alpha-Mediated RelB/APOBEC3B Down-regulation Allows Hepatitis B Virus Persistence.
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Riedl T, Faure-Dupuy S, Rolland M, Schuehle S, Hizir Z, Calderazzo S, Zhuang X, Wettengel J, Lopez MA, Barnault R, Mirakaj V, Prokosch S, Heide D, Leuchtenberger C, Schneider M, Heßling B, Stottmeier B, Wessbecher IM, Schirmacher P, McKeating JA, Protzer U, Durantel D, Lucifora J, Dejardin E, and Heikenwalder M
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- Amino Acids, Dicarboxylic pharmacology, Animals, Cell Line, Cytidine Deaminase metabolism, DNA, Circular metabolism, Down-Regulation, Gene Knockdown Techniques, Hepatitis B virus, Hepatitis B, Chronic metabolism, Hepatitis B, Chronic virology, Humans, Hypoxia genetics, Hypoxia metabolism, Lymphotoxin beta Receptor agonists, Mice, Microbial Viability, Minor Histocompatibility Antigens metabolism, RNA, Messenger metabolism, Transcription Factor RelB drug effects, Transcription Factor RelB metabolism, Cytidine Deaminase genetics, Hepatitis B, Chronic genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Liver metabolism, Minor Histocompatibility Antigens genetics, Transcription Factor RelB genetics
- Abstract
Background and Aims: Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization., Approach and Results: We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator., Conclusions: In conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
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- 2021
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20. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.
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Pinyol R, Torrecilla S, Wang H, Montironi C, Piqué-Gili M, Torres-Martin M, Wei-Qiang L, Willoughby CE, Ramadori P, Andreu-Oller C, Taik P, Lee YA, Moeini A, Peix J, Faure-Dupuy S, Riedl T, Schuehle S, Oliveira CP, Alves VA, Boffetta P, Lachenmayer A, Roessler S, Minguez B, Schirmacher P, Dufour JF, Thung SN, Reeves HL, Carrilho FJ, Chang C, Uzilov AV, Heikenwalder M, Sanyal A, Friedman SL, Sia D, and Llovet JM
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- Aged, Aged, 80 and over, Carcinoma, Hepatocellular etiology, Female, Humans, Liver Neoplasms etiology, Liver Neoplasms genetics, Male, Middle Aged, Molecular Biology methods, Non-alcoholic Fatty Liver Disease complications, Risk Factors, Carcinoma, Hepatocellular genetics, Molecular Biology statistics & numerical data, Non-alcoholic Fatty Liver Disease genetics
- Abstract
Background and Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies., Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays., Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved., Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature., Lay Summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC., Competing Interests: Conflict of interest J.M.L. receives research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Leerink Swann LLC, Fortress Biotech, Nucleix, Can-Fite Biopharma, Sirtex, Mina Alpha Ltd and AstraZeneca. S.L.F consults for the following companies: 89 Bio, Amgen, Axcella Health, Blade Therapeutics, Bristol Myers Squibb, Can-Fite Biopharma, ChemomAb, Escient Pharmaceuticals, Forbion, Foresite laboratories, Galmed, Gordian Biotechnology, Glycotest, Glympse Bio, Hepgene, In sitro, Morphic Therapeutics, North Sea Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Scholar Rock Surrozen. He has stock options in the following companies: Blade Therapeutics, Escient, Galectin, Galmed, Genfit, Glympse, Hepgene, Lifemax, Metacrine, Morphic Therapeutics, Nimbus, North Sea Therapeutics, Scholar Rock, Surrozen. He receives research support from Morphic Therapeutics, Novo Nordisk, and Galmed, and has an SBIR grant with Abalone Bio. A.L. is a consultant for Neuwave and Histosonics. C.P.M.S.O. consults for Bayer, Novartis, Novonordisk, Allergan, Pfizer, Roche and Zambon. P.S. is receiving research grants from BMS, Roche, Incyte, Chugai and consulting fees from BMS, MSD, Incyte, Janssen, Roche, AstraZeneca and Amgen. H.W., P.T., and A.V.U. are or were salaried employees of Sema4 at the time of the study. H.W., P.T., and A.V.U. hold Sema4 stock options. B.M. received consultancy fees from Bayer-Shering Pharma, and speaker fees from Eisai and MSD. The rest of authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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21. Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p.
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Faure-Dupuy S, Riedl T, Rolland M, Hizir Z, Reisinger F, Neuhaus K, Schuehle S, Remouchamps C, Gillet N, Schönung M, Stadler M, Wettengel J, Barnault R, Parent R, Schuster LC, Farhat R, Prokosch S, Leuchtenberger C, Öllinger R, Engleitner T, Rippe K, Rad R, Unger K, Tscharahganeh D, Lipka DB, Protzer U, Durantel D, Lucifora J, Dejardin E, and Heikenwälder M
- Abstract
Background & Aims: Immune-mediated induction of cytidine deaminase APOBEC3B (A3B) expression leads to HBV covalently closed circular DNA (cccDNA) decay. Here, we aimed to decipher the signalling pathway(s) and regulatory mechanism(s) involved in A3B induction and related HBV control., Methods: Differentiated HepaRG cells (dHepaRG) knocked-down for NF-κB signalling components, transfected with siRNA or micro RNAs (miRNA), and primary human hepatocytes ± HBV or HBVΔX or HBV-RFP, were treated with lymphotoxin beta receptor (LTβR)-agonist (BS1). The biological outcomes were analysed by reverse transcriptase-qPCR, immunoblotting, luciferase activity, chromatin immune precipitation, electrophoretic mobility-shift assay, targeted-bisulfite-, miRNA-, RNA-, genome-sequencing, and mass-spectrometry., Results: We found that canonical and non-canonical NF-κB signalling pathways are mandatory for A3B induction and anti-HBV effects. The degree of immune-mediated A3B production is independent of A3B promoter demethylation but is controlled post-transcriptionally by the miRNA 138-5p expression (hsa-miR-138-5p), promoting A3B mRNA decay. Hsa-miR-138-5p over-expression reduced A3B levels and its antiviral effects. Of note, established infection inhibited BS1-induced A3B expression through epigenetic modulation of A3B promoter. Twelve days of treatment with a LTβR-specific agonist BS1 is sufficient to reduce the cccDNA pool by 80% without inducing significant damages to a subset of cancer-related host genes. Interestingly, the A3B-mediated effect on HBV is independent of the transcriptional activity of cccDNA as well as on rcDNA synthesis., Conclusions: Altogether, A3B represents the only described enzyme to target both transcriptionally active and inactive cccDNA. Thus, inhibiting hsa-miR-138-5p expression should be considered in the combinatorial design of new therapies against HBV, especially in the context of immune-mediated A3B induction., Lay Summary: Immune-mediated induction of cytidine deaminase APOBEC3B is transcriptionally regulated by NF-κB signalling and post-transcriptionally downregulated by hsa-miR-138-5p expression, leading to cccDNA decay. Timely controlled APOBEC3B-mediated cccDNA decay occurs independently of cccDNA transcriptional activity and without damage to a subset of cancer-related genes. Thus, APOBEC3B-mediated cccDNA decay could offer an efficient therapeutic alternative to target hepatitis B virus chronic infection., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)
- Published
- 2021
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22. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control.
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Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Neuhaus K, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, and Heikenwalder M
- Subjects
- Adult, Animals, Cells, Cultured, Disease Models, Animal, Female, Gene Knockout Techniques, Genotype, Hepatitis C, Chronic virology, Humans, I-kappa B Kinase deficiency, I-kappa B Kinase genetics, Lymphocytic Choriomeningitis virology, Male, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Young Adult, Hepacivirus genetics, Hepatitis C, Chronic genetics, Hepatitis C, Chronic immunology, Hepatocytes immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus physiology, NF-kappa B p50 Subunit genetics, Polymorphism, Single Nucleotide, Transcription Factor RelA metabolism, Virus Replication genetics
- Abstract
Background & Aims: Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes., Methods: Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (Ikkβ
ΔHep ) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IfnarΔHep ), or interferon-α/β signaling in myeloid cells-(IfnarΔMyel ) were infected., Results: Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected IkkβΔHep livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8+ T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKβ, demonstrating a hepatocyte-intrinsic effect. Similar to livers of IkkβΔHep mice, enhanced hepatocytic LCMV accumulation was observed in livers of IfnarΔHep mice, whereas IfnarΔMyel mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/β-mediated inhibition of HBV replication in vitro., Conclusions: Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/β signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance., Lay Summary: Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication., Competing Interests: Conflict of interest The following authors declare no competing financial interests: S.N., T.O., S.F.D, P.J., T.R., K.L., H.X., I.S., P.S., F.L., A.P., P.Sh., M.R., A.M., K.B., P.B., S.L., D.D., R.F., A.W., D.L., T.K., P.St., U.P, D.W., B.H., M.B., K.B., L.M.A., J.N., Z.A., M.R., E.D., P.L., K.L., M.K., J.L., U.K., P.K., M.H. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020. Published by Elsevier B.V.)- Published
- 2020
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23. Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection.
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Faure-Dupuy S, Delphin M, Aillot L, Dimier L, Lebossé F, Fresquet J, Parent R, Matter MS, Rivoire M, Bendriss-Vermare N, Salvetti A, Heide D, Flores L, Klumpp K, Lam A, Zoulim F, Heikenwälder M, Durantel D, and Lucifora J
- Subjects
- Cells, Cultured, DNA, Viral isolation & purification, Humans, Immunohistochemistry, Immunomodulation, Interleukin-10, Interleukin-1beta, Mononuclear Phagocyte System immunology, Cell Differentiation immunology, Hepatitis B virus physiology, Hepatitis B, Chronic immunology, Hepatitis B, Chronic pathology, Kupffer Cells immunology, Kupffer Cells pathology, Macrophage Activation immunology, Monocytes immunology, Monocytes pathology
- Abstract
Background & Aims: Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively)., Methods: PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses., Results: HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1β, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes., Conclusions: Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection., Lay Summary: Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1β, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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24. Liver macrophages: Friend or foe during hepatitis B infection?
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Faure-Dupuy S, Durantel D, and Lucifora J
- Subjects
- Hepatitis B therapy, Hepatitis B virus, Host-Pathogen Interactions, Humans, Immune Tolerance, Immunity, Innate, Hepatitis B immunology, Kupffer Cells immunology, Liver cytology, Macrophages immunology
- Abstract
The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over the past decades, major advances have been made in the understanding of Hepatitis B virus life cycle in hepatocytes. Beside these parenchymal cells, the liver also contains resident and infiltrating myeloid cells involved in immune responses to pathogens and much less is known about their interplay with Hepatitis B virus. In this review, we summarized and discussed the current knowledge of the role of liver macrophages (including Kupffer cells and liver monocyte-derived macrophages), in HBV infection. While it is still unclear if liver macrophages play a role in the establishment and persistence of HBV infection, several studies disclosed data suggesting that HBV would favour liver macrophage anti-inflammatory phenotypes and thereby increase liver tolerance. In addition, alternatively activated liver macrophages might also play in the long term a key role in hepatitis B-associated pathogenesis, especially through the activation of hepatic stellate cells. Therapies aiming at a transient activation of pro-inflammatory liver macrophages should therefore be considered for the treatment of chronic HBV infection., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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25. Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines.
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Faure-Dupuy S, Vegna S, Aillot L, Dimier L, Esser K, Broxtermann M, Bonnin M, Bendriss-Vermare N, Rivoire M, Passot G, Lesurtel M, Mabrut JY, Ducerf C, Salvetti A, Protzer U, Zoulim F, Durantel D, and Lucifora J
- Subjects
- Cell Line, Cells, Cultured, Cellular Microenvironment, Humans, Immunity, Innate, Pathogen-Associated Molecular Pattern Molecules immunology, Primary Cell Culture, Receptors, Pattern Recognition metabolism, Transcriptome, Endothelial Cells physiology, Hepatic Stellate Cells physiology, Hepatocytes physiology, Kupffer Cells physiology, Liver immunology, Macrophages physiology, Receptors, Pattern Recognition genetics
- Abstract
Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development., (© 2018 S. Karger AG, Basel.)
- Published
- 2018
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26. Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts.
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Faure-Dupuy S, Lucifora J, and Durantel D
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- Animals, Dendritic Cells immunology, Hepatitis B virus physiology, Hepatitis B, Chronic immunology, Hepatitis B, Chronic therapy, Host-Pathogen Interactions, Humans, Killer Cells, Natural immunology, Liver cytology, Mice, Natural Killer T-Cells immunology, Hepatitis B immunology, Hepatitis B therapy, Hepatitis B virus immunology, Immunity, Innate, Liver immunology, Liver virology
- Abstract
The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity.
- Published
- 2017
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27. Characterization of the Inflammasome in Human Kupffer Cells in Response to Synthetic Agonists and Pathogens.
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Zannetti C, Roblot G, Charrier E, Ainouze M, Tout I, Briat F, Isorce N, Faure-Dupuy S, Michelet M, Marotel M, Kati S, Schulz TF, Rivoire M, Traverse-Glehen A, Luangsay S, Alatiff O, Henry T, Walzer T, Durantel D, and Hasan U
- Subjects
- Cells, Cultured, DNA-Binding Proteins metabolism, Humans, Immunity, Innate, Interferon Regulatory Factor-7 metabolism, Interleukin-18 metabolism, Interleukin-1beta metabolism, Interleukin-8 genetics, Interleukin-8 metabolism, Lymphocyte Activation, Hepatitis B virus immunology, Hepatitis B, Chronic immunology, Inflammasomes metabolism, Killer Cells, Natural immunology, Kupffer Cells physiology, Liver immunology
- Abstract
The liver is the largest gland in the human body and functions as an innate immune organ. Liver macrophages called Kupffer cells (KC) constitute the largest group of macrophages in the human body. Innate immune responses involving KC represent the first line of defense against pathogens in the liver. Human monocyte-derived macrophages have been used to characterize inflammasome responses that lead to the release of the proinflammatory cytokines IL-1β and IL-18, but it has not yet been determined whether human KC contain functional inflammasomes. We show, to our knowledge for the first time, that KC express genes and proteins that make up several different inflammasome complexes. Moreover, activation of KC in response to the absent in melanoma 2 (AIM2) inflammasome led to the production of IL-1β and IL-18, which activated IL-8 transcription and hepatic NK cell activity, respectively. Other inflammasome responses were also activated in response to selected bacteria and viruses. However, hepatitis B virus inhibited the AIM2 inflammasome by reducing the mRNA stability of IFN regulatory factor 7, which regulated AIM2 transcription. These data demonstrate the production of IL-1β and IL-18 in KC, suggesting that KC contain functional inflammasomes that could be important players in the innate immune response following certain infections of the liver. We think our findings could potentially aid therapeutic approaches against chronic liver diseases that activate the inflammasome., (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Published
- 2016
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28. [gMDSCs act as metabolic regulators of hepatitis B virus immunopathology].
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Faure-Dupuy S and Lucifora J
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- Humans, Liver immunology, Liver pathology, Liver virology, Granulocyte Precursor Cells immunology, Hepatitis B immunology, Hepatitis B virus immunology, Myeloid-Derived Suppressor Cells immunology
- Published
- 2016
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29. Early inhibition of hepatocyte innate responses by hepatitis B virus.
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Luangsay S, Gruffaz M, Isorce N, Testoni B, Michelet M, Faure-Dupuy S, Maadadi S, Ait-Goughoulte M, Parent R, Rivoire M, Javanbakht H, Lucifora J, Durantel D, and Zoulim F
- Subjects
- Cell Line, Cells, Cultured, Gene Expression, Hepatitis B Surface Antigens genetics, Hepatitis B Surface Antigens immunology, Hepatitis B e Antigens genetics, Hepatitis B e Antigens immunology, Hepatitis B virus genetics, Hepatitis B virus pathogenicity, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Interleukin-6 biosynthesis, RNA, Double-Stranded genetics, RNA, Double-Stranded immunology, Hepatitis B virus immunology, Hepatocytes immunology, Hepatocytes virology, Immunity, Innate genetics
- Abstract
Background & Aims: The outcome of hepatitis B virus (HBV) infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated., Methods: We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24h of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon stimulated genes. Experiments were also performed in the presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses., Results: We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on Toll-like receptor 3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication., Conclusions: Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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