A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control

Namineni, Sukumar; O’Connor, Tracy; Faure-Dupuy, Suzanne; Johansen, Pål; Riedl, Tobias; Liu, Kaijing; Xu, Haifeng; Singh, Indrabahadur; Shinde, Prashant V.; Li, Fanghui; Pandyra, Aleksandra A.; Sharma, Piyush; Ringelhan, Marc; Muschaweckh, Andreas; Borst, Katharina; Blank, Patrick; Lampl, Sandra; Neuhaus, K; Durantel, David; Farhat, Rayan; Weber, Achim; Lenggenhager, Daniela; Kündig, Thomas M.; Staeheli, Peter; Protzer, Ulrike; Wohlleber, Dirk; Holzmann, Bernhard; Binder, Marco; Breuhahn, Kai; Assmus, Lisa Mareike; Nattermann, Jacob; Abdullah, Zeinab; Rolland, Maude; Dejardin, Emmanuel; Lang, Philipp A.; Lang, Karl S.; Karin, Michael; Kalinke, Ulrich; Knolle, Percy; Heikenwälder, Mathias

doi:10.1016/j.jhep.2019.12.019

Cited by 19 publications

(27 citation statements)

References 61 publications

(79 reference statements)

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“…2C). Interestingly, TPCA-1, an IKKb inhibitor we already used previously, 34,35 abrogated the antiviral effect of Pam3CSK4 and BS1 on HDV (Fig. 2D).…”

Section: Resultsmentioning

confidence: 51%

Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro

et al. 2022

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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.

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“…2C). Interestingly, TPCA-1, an IKKb inhibitor we already used previously, 34,35 abrogated the antiviral effect of Pam3CSK4 and BS1 on HDV (Fig. 2D).…”

Section: Resultsmentioning

confidence: 51%

Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro

et al. 2022

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“…The generation of double-sgRNA containing vectors for the knockout cell line generation was described previously. 13 In short, sgRNAs were chosen based on high scoring and no high scoring off-targets using the CHOPCHOP version 2 web tool. 14 These sgRNAs were inserted into pUSEPR (generous gift from Dr. Tscharaganeh, DKFZ, Heidelberg, unpublished) based on methods as described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, HepaRG cells were transduced with pLenti6-TR to introduce the tetracyclin repressor (TetR), and subsequently with pLenti4/TO/V5 (Invitrogen), in which the coding sequence of an N-terminally 3x FLAG-tagged Cas9 was inserted between the EcoRI and XhoI sites of the vector. The generation of double-sgRNA containing vectors for the knock-out cell line generation was described previously [13]. In short, sgRNAs were chosen based on high scoring and no high scoring off-targets using CHOPCHOP v2 web tool [14].…”

Section: Transgenic Cell Line Preparationmentioning

confidence: 99%

“…in a combinatorial regiment with other treatments) that should be considered to ensure the full functionality of LTβR agonists-based treatments. These SNVs were then filtered to identify SNVs, that occur in all samples with a number of alleles (NAF) > 5% and a coverage > 30 (2,404), only in all treated samples (13) and only in all 'not treated' samples (12). 439 SNVs were not found in all samples but they were not specific to either of the two groups.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

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Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…IFN expression and ISG upregulation were also induced when TLR3 recognized HCV RNA in endosomes [63,64]. A recent study in mice that lacked canonical NF-κB signaling showed that the hepatocyte-intrinsic NF-κB was a critical amplifier of type I IFN signaling; it induced ISG upregulation, the recruitment of activated immune cells, and viral clearance [65].…”

Section: Host Factors Involved In Hcv Sensing and Ifn Productionmentioning

confidence: 99%

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

Sung

Shin

2020

IJMS

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When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.

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A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control

Cited by 19 publications

References 61 publications

Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro

Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro

Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

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