Cells

Research

Jump to: Review

18 pages, 9856 KiB

Open AccessArticle

Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity

by Sebastian Maximilian Altstetter, Oliver Quitt, Francesca Pinci, Veit Hornung, Aaron Michael Lucko, Karin Wisskirchen, Stephanie Jung and Ulrike Protzer

Cells 2021, 10(11), 3253; https://doi.org/10.3390/cells10113253 - 20 Nov 2021

Cited by 2 | Viewed by 2656

Abstract

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the [...] Read more.

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Graphical abstract

18 pages, 3372 KiB

Open AccessArticle

Characterization of RNA Sensing Pathways in Hepatoma Cell Lines and Primary Human Hepatocytes

by Wiebke Nicolay, Rebecca Moeller, Sina Kahl, Florian W. R. Vondran, Thomas Pietschmann, Stefan Kunz and Gisa Gerold

Cells 2021, 10(11), 3019; https://doi.org/10.3390/cells10113019 - 04 Nov 2021

Cited by 9 | Viewed by 2539

Abstract

The liver is targeted by several human pathogenic RNA viruses for viral replication and dissemination; despite this, the extent of innate immune sensing of RNA viruses by human hepatocytes is insufficiently understood to date. In particular, for highly human tropic viruses such as [...] Read more.

The liver is targeted by several human pathogenic RNA viruses for viral replication and dissemination; despite this, the extent of innate immune sensing of RNA viruses by human hepatocytes is insufficiently understood to date. In particular, for highly human tropic viruses such as hepatitis C virus, cell culture models are needed to study immune sensing. However, several human hepatoma cell lines have impaired RNA sensing pathways and fail to mimic innate immune responses in the human liver. Here we compare the RNA sensing properties of six human hepatoma cell lines, namely Huh-6, Huh-7, HepG2, HepG2-HFL, Hep3B, and HepaRG, with primary human hepatocytes. We show that primary liver cells sense RNA through retinoic acid-inducible gene I (RIG-I) like receptor (RLR) and Toll-like receptor 3 (TLR3) pathways. Of the tested cell lines, Hep3B cells most closely mimicked the RLR and TLR3 mediated sensing in primary hepatocytes. This was shown by the expression of RLRs and TLR3 as well as the expression and release of bioactive interferon in primary hepatocytes and Hep3B cells. Our work shows that Hep3B cells partially mimic RNA sensing in primary hepatocytes and thus can serve as in vitro model to study innate immunity to RNA viruses in hepatocytes. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

26 pages, 2047 KiB

Open AccessArticle

Comparative Analysis of Six IRF Family Members in Alveolar Epithelial Cell-Intrinsic Antiviral Responses

by Sandra Wüst, Paulina Schad, Sandy Burkart and Marco Binder

Cells 2021, 10(10), 2600; https://doi.org/10.3390/cells10102600 - 30 Sep 2021

Cited by 13 | Viewed by 3802

Abstract

Host cell-intrinsic antiviral responses are largely mediated by pattern-recognition receptor (PRR) signaling and the interferon (IFN) system. The IFN regulatory factor (IRF) family of transcription factors takes up a central role in transcriptional regulation of antiviral innate immunity. IRF3 and IRF7 are known [...] Read more.

Host cell-intrinsic antiviral responses are largely mediated by pattern-recognition receptor (PRR) signaling and the interferon (IFN) system. The IFN regulatory factor (IRF) family of transcription factors takes up a central role in transcriptional regulation of antiviral innate immunity. IRF3 and IRF7 are known to be key players downstream of PRRs mediating the induction of type I and III IFNs. IFN signaling then requires IRF9 for the expression of the full array of interferon stimulated genes (ISGs) ultimately defining the antiviral state of the cell. Other members of the IRF family clearly play a role in mediating or modulating IFN responses, such as IRF1, IRF2 or IRF5, however their relative contribution to mounting a functional antiviral response is much less understood. In this study, we systematically and comparatively assessed the impact of six members of the IRF family on antiviral signaling in alveolar epithelial cells. We generated functional knockouts of IRF1, -2, -3, -5, -7, and -9 in A549 cells, and measured their impact on the expression of IFNs and further cytokines, ISGs and other IRFs, as well as on viral replication. Our results confirmed the vital importance of IRF3 and IRF9 in establishing an antiviral state, whereas IRF1, 5 and 7 were largely dispensable. The previously described inhibitory activity of IRF2 could not be observed in our experimental system. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

14 pages, 2084 KiB

Open AccessCommunication

Antiviral Activity of Influenza A Virus Defective Interfering Particles against SARS-CoV-2 Replication In Vitro through Stimulation of Innate Immunity

by Ulfert Rand, Sascha Young Kupke, Hanna Shkarlet, Marc Dominique Hein, Tatjana Hirsch, Pavel Marichal-Gallardo, Luka Cicin-Sain, Udo Reichl and Dunja Bruder

Cells 2021, 10(7), 1756; https://doi.org/10.3390/cells10071756 - 11 Jul 2021

Cited by 20 | Viewed by 5697

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, worldwide vaccine availability is still limited. Moreover, immune [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, worldwide vaccine availability is still limited. Moreover, immune escape variants of the virus are emerging against which the current vaccines may confer only limited protection. Further, existing antivirals and treatment options against COVID-19 show only limited efficacy. Influenza A virus (IAV) defective interfering particles (DIPs) were previously proposed not only for antiviral treatment of the influenza disease but also for pan-specific treatment of interferon (IFN)-sensitive respiratory virus infections. To investigate the applicability of IAV DIPs as an antiviral for the treatment of COVID-19, we conducted in vitro co-infection experiments with cell culture-derived DIPs and the IFN-sensitive SARS-CoV-2 in human lung cells. We show that treatment with IAV DIPs leads to complete abrogation of SARS-CoV-2 replication. Moreover, this inhibitory effect was dependent on janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Further, our results suggest boosting of IFN-induced antiviral activity by IAV DIPs as a major contributor in suppressing SARS-CoV-2 replication. Thus, we propose IAV DIPs as an effective antiviral agent for treatment of COVID-19, and potentially also for suppressing the replication of new variants of SARS-CoV-2. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

Review

Jump to: Research

15 pages, 865 KiB

Open AccessReview

Anti-Viral Pattern Recognition Receptors as Therapeutic Targets

by Conor Hennessy and Declan P. McKernan

Cells 2021, 10(9), 2258; https://doi.org/10.3390/cells10092258 - 31 Aug 2021

Cited by 18 | Viewed by 5465

Abstract

Pattern recognition receptors (PRRs) play a central role in the inflammation that ensues following microbial infection by their recognition of molecular patterns present in invading microorganisms but also following tissue damage by recognising molecules released during disease states. Such receptors are expressed in [...] Read more.

Pattern recognition receptors (PRRs) play a central role in the inflammation that ensues following microbial infection by their recognition of molecular patterns present in invading microorganisms but also following tissue damage by recognising molecules released during disease states. Such receptors are expressed in a variety of cells and in various compartments of these cells. PRR binding of molecular patterns results in an intracellular signalling cascade and the eventual activation of transcription factors and the release of cytokines, chemokines, and vasoactive molecules. PRRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. They are also key to reacting to infection and in stimulating the immune system when needed. Therefore, targeting PRRs offers a potential therapeutic approach for chronic inflammatory disease, infections and as vaccine adjuvants. In this review, the current knowledge on anti-viral PRRs and their signalling pathways is reviewed. Finally, compounds that target PRRs and that have been tested in clinical trials for chronic infections and as adjuvants in vaccine trials are discussed. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

22 pages, 1226 KiB

Open AccessFeature PaperReview

Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections

by Maximilian Hirschenberger, Victoria Hunszinger and Konstantin Maria Johannes Sparrer

Cells 2021, 10(8), 2134; https://doi.org/10.3390/cells10082134 - 19 Aug 2021

Cited by 28 | Viewed by 7975

Abstract

Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once [...] Read more.

Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

20 pages, 1199 KiB

Open AccessReview

Innate Immune Responses to Herpesvirus Infection

by Christine M. O’Connor and Ganes C. Sen

Cells 2021, 10(8), 2122; https://doi.org/10.3390/cells10082122 - 18 Aug 2021

Cited by 10 | Viewed by 4068

Abstract

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This [...] Read more.

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

12 pages, 877 KiB

Open AccessReview

Role of Alternative Splicing in Regulating Host Response to Viral Infection

by Kuo-Chieh Liao and Mariano A. Garcia-Blanco

Cells 2021, 10(7), 1720; https://doi.org/10.3390/cells10071720 - 08 Jul 2021

Cited by 14 | Viewed by 3931

Abstract

The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the [...] Read more.

The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation. Full article

(This article belongs to the Special Issue Signaling Pathways in Host Cell Antiviral Responses)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Signaling Pathways in Host Cell Antiviral Responses

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI