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5 pages, 637 KiB

Open AccessEditorial

Interferons in Viral Infections

by Pracheta Sengupta and Saurabh Chattopadhyay

Viruses 2024, 16(3), 451; https://doi.org/10.3390/v16030451 - 14 Mar 2024

Cited by 3 | Viewed by 2082

Abstract

Interferons (IFNs) are cytokines that inhibit viral replication in host cells by triggering innate immune responses through the transcriptional induction of various IFN-stimulated genes (ISGs) [...] Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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Research

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18 pages, 3601 KiB

Open AccessArticle

Influence of Canonical and Non-Canonical IFNLR1 Isoform Expression on Interferon Lambda Signaling

by John Grayson Evans, Laura A. Novotny and Eric G. Meissner

Viruses 2023, 15(3), 632; https://doi.org/10.3390/v15030632 - 25 Feb 2023

Cited by 5 | Viewed by 2036

Abstract

Interferon lambdas (IFNLs) are innate immune cytokines that induce antiviral cellular responses by signaling through a heterodimer composed of IL10RB and the interferon lambda receptor 1 (IFNLR1). Multiple IFNLR1 transcriptional variants are expressed in vivo and are predicted to encode distinct protein isoforms [...] Read more.

Interferon lambdas (IFNLs) are innate immune cytokines that induce antiviral cellular responses by signaling through a heterodimer composed of IL10RB and the interferon lambda receptor 1 (IFNLR1). Multiple IFNLR1 transcriptional variants are expressed in vivo and are predicted to encode distinct protein isoforms whose function is not fully established. IFNLR1 isoform 1 has the highest relative transcriptional expression and encodes the full-length functional form that supports canonical IFNL signaling. IFNLR1 isoforms 2 and 3 have lower relative expression and are predicted to encode signaling-defective proteins. To gain insight into IFNLR1 function and regulation, we explored how altering relative expression of IFNLR1 isoforms influenced the cellular response to IFNLs. To achieve this, we generated and functionally characterized stable HEK293T clones expressing doxycycline-inducible FLAG-tagged IFNLR1 isoforms. Minimal FLAG-IFNLR1 isoform 1 overexpression markedly increased IFNL3-dependent expression of antiviral and pro-inflammatory genes, a phenotype that could not be further augmented by expressing higher levels of FLAG-IFNLR1 isoform 1. Expression of low levels of FLAG-IFNLR1 isoform 2 led to partial induction of antiviral genes, but not pro-inflammatory genes, after IFNL3 treatment, a phenotype that was largely abrogated at higher FLAG-IFNLR1 isoform 2 expression levels. Expression of FLAG-IFNLR1 isoform 3 partially augmented antiviral gene expression after IFNL3 treatment. In addition, FLAG-IFNLR1 isoform 1 significantly reduced cellular sensitivity to the type-I IFN IFNA2 when overexpressed. These results identify a unique influence of canonical and non-canonical IFNLR1 isoforms on mediating the cellular response to interferons and provide insight into possible pathway regulation in vivo. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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24 pages, 4777 KiB

Open AccessArticle

Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α

by Marlies Boeren, Elise Van Breedam, Tamariche Buyle-Huybrecht, Marielle Lebrun, Pieter Meysman, Catherine Sadzot-Delvaux, Viggo F. Van Tendeloo, Geert Mortier, Kris Laukens, Benson Ogunjimi, Peter Ponsaerts and Peter Delputte

Viruses 2022, 14(11), 2517; https://doi.org/10.3390/v14112517 - 14 Nov 2022

Cited by 5 | Viewed by 2515

Abstract

Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent [...] Read more.

Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent stem cell (hiPSC)-derived neuronal culture model that allows axonal VZV infection of the neurons, thereby mimicking the natural route of infection. Using this model, we showed that hiPSC-neurons do not mount an effective interferon-mediated antiviral response following VZV infection. Indeed, in contrast to infection with Sendai virus, VZV infection of the hiPSC-neurons does not result in the upregulation of interferon-stimulated genes (ISGs) that have direct antiviral functions. Furthermore, the hiPSC-neurons do not produce interferon-α (IFNα), a major cytokine that is involved in the innate antiviral response, even upon its stimulation with strong synthetic inducers. In contrast, we showed that exogenous IFNα effectively limits VZV spread in the neuronal cell body compartment and demonstrated that ISGs are efficiently upregulated in these VZV-infected neuronal cultures that are treated with IFNα. Thus, whereas the cultured hiPSC neurons seem to be poor IFNα producers, they are good IFNα responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFNα for VZV infection control. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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13 pages, 2490 KiB

Open AccessArticle

A Hepatitis B Virus-Derived Peptide Can Inhibit Infection of Human Lung Cells with SARS-CoV-2 in a Type-1 Interferon-Dependent Manner

by Yu-Min Choi, Hyein Jeong, Uni Park, Nam-Hyuk Cho and Bum-Joon Kim

Viruses 2021, 13(7), 1227; https://doi.org/10.3390/v13071227 - 25 Jun 2021

Cited by 3 | Viewed by 3063

Abstract

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency [...] Read more.

The current COVID-19 pandemic has highlighted the urgent need to develop effective therapeutic strategies. We evaluated the in vitro antiviral effect against SARS-CoV-2 of a hepatitis B virus (HBV) hexamer peptide, Poly6, which is capable of eliciting an antiviral effect against human immunodeficiency virus -1 (HIV-1), as a novel HIV-1 integrase inhibitor, and a strong anticancer immune response in an IFN-I-dependent manner, as a novel potential adjuvant in anticancer immunotherapy. Here, we report that Poly6 exerts an anti-SARS-CoV-2 effect, with an estimated 50% inhibitory concentration of 2.617 µM, in the human bronchial epithelial cell line, Calu-3 but not in Vero-E6 cells, which are deficient in type 1 interferon (IFN-I) signaling. We proved via assays based on mRNA profiles, inhibitors, or blocking antibodies that Poly6 can exert an anti-SARS-CoV-2 effect in an IFN-I-dependent manner. We also found that Poly6 inhibits IL-6 production enhanced by SARS-CoV-2 in infected Calu-3 cells at both the transcription and the translation levels, mediated via IL-10 induction in an IFN-I-dependent manner. These results indicate the feasibility of Poly6 as an IFN-I-inducing COVID-19 drug with potent antiviral and anti-inflammatory activities. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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16 pages, 1735 KiB

Open AccessArticle

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

by Barkha Ramnani, Praveen Manivannan, Sarah Jaggernauth and Krishnamurthy Malathi

Viruses 2021, 13(2), 315; https://doi.org/10.3390/v13020315 - 18 Feb 2021

Cited by 4 | Viewed by 4373

Abstract

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated [...] Read more.

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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Review

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12 pages, 1801 KiB

Open AccessReview

How Different Pathologies Are Affected by IFIT Expression

by Justin H. Franco, Saurabh Chattopadhyay and Zhixing K. Pan

Viruses 2023, 15(2), 342; https://doi.org/10.3390/v15020342 - 25 Jan 2023

Cited by 10 | Viewed by 3596

Abstract

The type-I interferon (IFN) system represents the first line of defense against viral pathogens. Recognition of the virus initiates complex signaling pathways that result in the transcriptional induction of IFNs, which are then secreted. Secreted IFNs stimulate nearby cells and result in the [...] Read more.

The type-I interferon (IFN) system represents the first line of defense against viral pathogens. Recognition of the virus initiates complex signaling pathways that result in the transcriptional induction of IFNs, which are then secreted. Secreted IFNs stimulate nearby cells and result in the production of numerous proinflammatory cytokines and antiviral factors. Of particular note, IFN-induced tetratricopeptide repeat (IFIT) proteins have been thoroughly studied because of their antiviral activity against different viral pathogens. Although classically studied as an antiviral protein, IFIT expression has recently been investigated in the context of nonviral pathologies, such as cancer and sepsis. In oral squamous cell carcinoma (OSCC), IFIT1 and IFIT3 promote metastasis, while IFIT2 exhibits the opposite effect. The role of IFIT proteins during bacterial/fungal sepsis is still under investigation, with studies showing conflicting roles for IFIT2 in disease severity. In the setting of viral sepsis, IFIT proteins play a key role in clearing viral infection. As a result, many viral pathogens, such as SARS-CoV-2, employ mechanisms to inhibit the type-I IFN system and promote viral replication. In cancers that are characterized by upregulated IFIT proteins, medications that decrease IFIT expression may reduce metastasis and improve survival rates. Likewise, in cases of viral sepsis, therapeutics that increase IFIT expression may improve viral clearance and reduce the risk of septic shock. By understanding the effect of IFIT proteins in different pathologies, novel therapeutics can be developed to halt disease progression. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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15 pages, 6244 KiB

Open AccessReview

HSV Replication: Triggering and Repressing STING Functionality

by Eric Krawczyk, Chase Kangas and Bin He

Viruses 2023, 15(1), 226; https://doi.org/10.3390/v15010226 - 13 Jan 2023

Cited by 5 | Viewed by 2874

Abstract

Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein [...] Read more.

Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein stimulator of interferon genes (STING) functions as a mediator of the antiviral response by inducing interferon (IFN) as well as IFN-stimulated genes. Emerging evidence suggests that during HSV infection, dsDNA derived from either the virus or the host itself ultimately activates STING signaling. While a complex regulatory circuit is in operation, HSV has evolved several mechanisms to neutralize the STING-mediated antiviral response. Within this review, we highlight recent progress involving HSV interactions with the STING pathway, with a focus on how STING influences HSV replication and pathogenesis. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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24 pages, 2998 KiB

Open AccessReview

Transcriptional and Non-Transcriptional Activation, Posttranslational Modifications, and Antiviral Functions of Interferon Regulatory Factor 3 and Viral Antagonism by the SARS-Coronavirus

by Anna Glanz, Sukanya Chakravarty, Merina Varghese, Anita Kottapalli, Shumin Fan, Ritu Chakravarti and Saurabh Chattopadhyay

Viruses 2021, 13(4), 575; https://doi.org/10.3390/v13040575 - 29 Mar 2021

Cited by 31 | Viewed by 6270

Abstract

The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the [...] Read more.

The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3^−/− mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNβ), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3′s RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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Other

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5 pages, 1382 KiB

Open AccessCommentary

Inflammatory Control of Viral Infection

by Sukanya Chakravarty, Ritu Chakravarti and Saurabh Chattopadhyay

Viruses 2023, 15(7), 1579; https://doi.org/10.3390/v15071579 - 20 Jul 2023

Cited by 4 | Viewed by 1427

Abstract

Inflammatory responses during virus infection differentially impact the host. Managing inflammatory responses is essential in controlling viral infection and related diseases. Recently, we identified a cellular anti-inflammatory mechanism, RIKA (Repression of IRF3-mediated inhibition of NF-κB activity), which controls viral inflammation and pathogenesis. The [...] Read more.

Inflammatory responses during virus infection differentially impact the host. Managing inflammatory responses is essential in controlling viral infection and related diseases. Recently, we identified a cellular anti-inflammatory mechanism, RIKA (Repression of IRF3-mediated inhibition of NF-κB activity), which controls viral inflammation and pathogenesis. The RIKA function of IRF3 may be explored further in other inflammatory diseases beyond viral infection. Full article

(This article belongs to the Special Issue Interferons in Viral Infections)

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