Transcriptome analysis of senecavirus A-infected cells: Type I interferon is a critical anti-viral factor

Dengue virus (DENV) is a mosquito-borne flavivirus that causes an acute febrile disease in humans, characterized by musculoskeletal pain, headache, rash and leukopenia. The cause of myalgia during DENV infection is still unknown. To determine whether DENV can infect primary muscle cells, human muscle satellite cells were exposed to DENV in vitro. The results demonstrated for the first time high-efficiency infection and replication of DENV in human primary muscle satellite cells. Changes in global gene expression were also examined in these cells following DENV infection using Affymetrix GeneChip analysis. The differentially regulated genes belonged to two main functional categories: cell growth and development, and antiviral type I interferon (IFN) response genes. Increased expression of the type I IFN response genes for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), melanoma-derived antigen 5 (MDA-5), IFN-γ-inducible protein 10 (IP-10), galectin 3 soluble binding protein (LGals3BP) and IFN response factor 7 (IRF7) was confirmed by quantitative RT-PCR. Furthermore, higher levels of cell-surface-bound intracellular adhesion molecule-1 (ICAM-1) and soluble ICAM-1 in the cell-culture medium were detected following DENV infection. However, DENV infection impaired the ability of the infected cells in the culture medium to upregulate cell-surface expression of MHC I molecules, suggesting a possible mechanism of immune evasion by DENV. The findings of this study warrant further clinical research to identify whether muscle cells are targets for DENV infection during the acute stage of the disease in vivo.

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Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation

Journal of Virology ◽

10.1128/jvi.00258-20 ◽

2020 ◽

Vol 94 (11) ◽

Author(s):

XueQiao Liu ◽

Tomohiko Sadaoka ◽

Tammy Krogmann ◽

Jeffrey I. Cohen

Keyword(s):

Virus Infection ◽

Type I Interferon ◽

Tegument Protein ◽

Type I ◽

Type I Ifn ◽

Virus Reactivation ◽

Ebv Infection ◽

Ebv Reactivation ◽

Stat3 Phosphorylation ◽

Infected Cells

ABSTRACT Interferon alpha (IFN-α) and IFN-β are type I IFNs that are induced by virus infection and are important in the host’s innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation. IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host’s antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.

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Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins

Journal of Virology ◽

10.1128/jvi.00882-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12696-12703 ◽

Cited By ~ 134

Author(s):

Luis Martínez-Sobrido ◽

Panagiotis Giannakas ◽

Beatrice Cubitt ◽

Adolfo García-Sastre ◽

Juan Carlos de la Torre

Keyword(s):

New World ◽

Nuclear Translocation ◽

Type I Interferon ◽

Lymphocytic Choriomeningitis ◽

Interferon Response ◽

Type I ◽

Regulatory Factor ◽

Interferon Induction ◽

Tacaribe Virus ◽

Infected Cells

ABSTRACT We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production.

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The VP3 Protein of Bluetongue Virus Associates with the MAVS Complex and Interferes with the RIG-I-Signaling Pathway

Viruses ◽

10.3390/v13020230 ◽

2021 ◽

Vol 13 (2) ◽

pp. 230

Author(s):

Marie Pourcelot ◽

Rayane Amaral Moraes ◽

Aurore Fablet ◽

Emmanuel Bréard ◽

Corinne Sailleau ◽

...

Keyword(s):

Bluetongue Virus ◽

Type I Interferon ◽

Type I ◽

Adapter Protein ◽

Structural Protein ◽

Innate Response ◽

Biting Midges ◽

Domestic Ruminants ◽

Infected Cells ◽

Culicoides Biting Midges

Bluetongue virus (BTV), an arbovirus transmitted by Culicoides biting midges, is a major concern of wild and domestic ruminants. While BTV induces type I interferon (alpha/beta interferon [IFN-α/β]) production in infected cells, several reports have described evasion strategies elaborated by this virus to dampen this intrinsic, innate response. In the present study, we suggest that BTV VP3 is a new viral antagonist of the IFN-β synthesis. Indeed, using split luciferase and coprecipitation assays, we report an interaction between VP3 and both the mitochondrial adapter protein MAVS and the IRF3-kinase IKKε. Overall, this study describes a putative role for the BTV structural protein VP3 in the control of the antiviral response.

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Influenza Virus Infection Enhances Antibody-Mediated NK Cell Functions via Type I Interferon-Dependent Pathways

Journal of Virology ◽

10.1128/jvi.02090-18 ◽

2018 ◽

Vol 93 (5) ◽

Cited By ~ 8

Author(s):

Sinthujan Jegaskanda ◽

Hillary A. Vanderven ◽

Hyon-Xhi Tan ◽

Sheilajen Alcantara ◽

Kathleen M. Wragg ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Nk Cells ◽

Nk Cell ◽

Type I Interferon ◽

A549 Cells ◽

Influenza Virus Infection ◽

Type I ◽

Cell Functions ◽

Infected Cells

ABSTRACT Natural killer (NK) cells are an important component in the control of influenza virus infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of CD16 on NK cells by antibody-coated influenza virus-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Increasing the potency of antibody-mediated NK cell activity could ultimately lead to improved control of influenza virus infection. To understand if NK cells can be functionally enhanced following exposure to influenza virus-infected cells, we cocultured human peripheral blood mononuclear cells (PBMCs) with influenza virus-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate antibody-dependent functions. Preincubation of PBMCs with influenza virus-infected cells markedly enhanced the ability of NK cells to respond to immune complexes containing hemagglutinin (HA) and anti-HA antibodies or transformed allogeneic cells in the presence or absence of a therapeutic monoclonal antibody. Cytokine multiplex, RNA sequencing, supernatant transfer, Transwell, and cytokine-blocking/cytokine supplementation experiments showed that type I interferons released from PBMCs were primarily responsible for the influenza virus-induced enhancement of antibody-mediated NK cell functions. Importantly, the influenza virus-mediated increase in antibody-dependent NK cell functionality was mimicked by the type I interferon agonist poly(I·C). We conclude that the type I interferon secretion induced by influenza virus infection enhances the capacity of NK cells to mediate ADCC and that this pathway could be manipulated to alter the potency of anti-influenza virus therapies and vaccines. IMPORTANCE Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza virus infection. We found that type I interferon released in response to influenza virus infection primes NK cells to become highly reactive to anti-influenza virus ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.

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Human Rhinovirus Attenuates the Type I Interferon Response by Disrupting Activation of Interferon Regulatory Factor 3

Journal of Virology ◽

10.1128/jvi.80.10.5021-5031.2006 ◽

2006 ◽

Vol 80 (10) ◽

pp. 5021-5031 ◽

Cited By ~ 22

Author(s):

Tao Peng ◽

Swathi Kotla ◽

Roger E. Bumgarner ◽

Kurt E. Gustin

Keyword(s):

Type I Interferon ◽

Transcriptional Response ◽

Interferon Regulatory Factor ◽

Alveolar Epithelial Cells ◽

Interferon Response ◽

Type I ◽

Regulatory Factor ◽

Full Spectrum ◽

Interferon Regulatory Factor 3 ◽

Infected Cells

ABSTRACT The type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-κB, interferon regulatory factor 3 (IRF-3), and ATF-2, which in turn activate transcription from the IFN-β promoter. Synthesis and subsequent secretion of IFN-β activate the Jak/STAT signaling pathway, resulting in the transcriptional induction of the full spectrum of antiviral gene products. We utilized high-density microarrays to examine the transcriptional response to rhinovirus type 14 (RV14) infection in HeLa cells, with particular emphasis on the type I interferon response and production of IFN-β. We found that, although RV14 infection results in altered levels of a wide variety of host mRNAs, induction of IFN-β mRNA or activation of the Jak/STAT pathway is not seen. Prior work has shown, and our results have confirmed, that NF-κB and ATF-2 are activated following infection. Since many viruses are known to target IRF-3 to inhibit the induction of IFN-β mRNA, we analyzed the status of IRF-3 in infected cells. IRF-3 was translocated to the nucleus and phosphorylated in RV14-infected cells. Despite this apparent activation, very little homodimerization of IRF-3 was evident following infection. Similar results in A549 lung alveolar epithelial cells demonstrated the biological relevance of these findings to RV14 pathogenesis. In addition, prior infection of cells with RV14 prevented the induction of IFN-β mRNA following treatment with double-stranded RNA, indicating that RV14 encodes an activity that specifically inhibits this innate host defense pathway. Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.

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Rotavirus NSP1 Inhibits Expression of Type I Interferon by Antagonizing the Function of Interferon Regulatory Factors IRF3, IRF5, and IRF7

Journal of Virology ◽

10.1128/jvi.02498-06 ◽

2007 ◽

Vol 81 (9) ◽

pp. 4473-4481 ◽

Cited By ~ 146

Author(s):

Mario Barro ◽

John T. Patton

Keyword(s):

Mammalian Cells ◽

Type I Interferon ◽

Common Element ◽

Type I ◽

Wild Type ◽

Regulatory Factor ◽

Poor Growth ◽

Infected Cells ◽

Growth Phenotype ◽

Dependent Processes

ABSTRACT Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the “master regulator” of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.

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IFITMs Inhibit Cell Fusion Mediated by Trophoblast Syncytins

10.1101/713032 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ashley Zani ◽

Lizhi Zhang ◽

Adam Kenney ◽

Temet M. McMichael ◽

Jesse J. Kwiek ◽

...

Keyword(s):

Virus Infection ◽

Fetal Development ◽

Type I Interferon ◽

Cell Structure ◽

Transmembrane Proteins ◽

Type I ◽

Multinucleated Cell ◽

Virus Infections ◽

Infected Cells ◽

Inhibit Cell Fusion

AbstractType I interferon (IFN) induced by virus infections during pregnancy causes placental damage, though the mechanisms and identities of IFN-stimulated genes that are involved remain under investigation. The IFN-induced transmembrane proteins (IFITMs) inhibit virus infections by preventing virus membrane fusion with cells and by inhibiting fusion of infected cells (syncytialization). Fusion of placental trophoblasts via expression of endogenous retroviral fusogens known as Syncytins forms the syncytiotrophoblast, a multinucleated cell structure essential for fetal development. We found that IFN blocks fusion of BeWo human placental trophoblasts. Stably-expressed IFITMs 1, 2, and 3 also blocked fusion of these trophoblasts, while making them more resistant to virus infections. Conversely, stable knockdown of IFITMs in BeWo trophoblasts increased their spontaneous fusion and allowed fusion in the presence of IFN, while also making the cells more susceptible to virus infection. Overall, our data demonstrate that IFITMs are anti-viral and anti-fusogenic in trophoblasts.

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Enterovirus 2Apro Cleavage of the YTHDF m6A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

mBio ◽

10.1128/mbio.00116-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Jonathan P. Kastan ◽

Martine W. Tremblay ◽

Michael C. Brown ◽

Joseph D. Trimarco ◽

Elena Y. Dobrikova ◽

...

Keyword(s):

Type I Interferon ◽

Biological Significance ◽

Cell Manipulation ◽

Type I ◽

Messenger Rnas ◽

Viral Translation ◽

Antiviral Immune Response ◽

Stat Signaling ◽

Infected Cells ◽

In Cells

ABSTRACT Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N6-methyladenosine (m6A) “readers” that regulate target mRNA fate. YTHDF protein cleavage occurs very early during infection, before viral translation is detected or cytopathogenic effects are observed. Preemptive YTHDF protein depletion enhanced viral translation and replication but only in cells with restrained viral translation, signs of inefficient 2A protease activity, and protective innate host immune responses. This effect corresponded with repression of interferon (IFN)-stimulated gene (ISG) induction, while type I/III IFN production was not significantly altered. Moreover, YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I, but not type II, IFN. YTHDF3 depletion’s stimulatory effect on viral dynamics was dampened by JAK/STAT blockade and enhanced by type I IFN pretreatment of cells. We propose that EV 2A proteases cleave YTHDF proteins to antagonize ISG induction in infected cells. IMPORTANCE It is believed that ∼7,000 messenger RNAs (mRNAs) are subject to N6-methyladenosine modification. The biological significance of this remains mysterious. The YTHDF m6A readers are three related proteins with high affinity for m6A-modified mRNA, yet their biological functions remain obscure. We discovered that polio/enteroviruses elicit very early proteolysis of YTHDF1 to 3 in infected cells. Our research demonstrates that YTHDF3 acts as a positive regulator of antiviral JAK/STAT signaling in response to positive single-strand RNA virus infection, enabling type I interferon (IFN)-mediated gene regulatory programs to unfurl in infected cells. Our observation of viral degradation of the YTHDF proteins demonstrates that they are key response modifiers in the innate antiviral immune response.

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B.1.1.7 and B.1.351 SARS-CoV-2 variants display enhanced Spike-mediated fusion

10.1101/2021.06.11.448011 ◽

2021 ◽

Author(s):

Maaran Michael Rajah ◽

Mathieu Hubert ◽

Elodie Bishop ◽

Nell Saunders ◽

Rémy Robinot ◽

...

Keyword(s):

Innate Immunity ◽

Monoclonal Antibodies ◽

Reference Strain ◽

Type I Interferon ◽

Transmembrane Proteins ◽

Viral Proteins ◽

Type I ◽

Cytopathic Effects ◽

Lung Abnormalities ◽

Infected Cells

SARS-CoV-2 B.1.1.7 (variant Alpha) and B.1.351 (variant Beta) have supplanted pre-existing strains in many countries. Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when infected cells fuse with adjacent cells. The fitness, cytopathic effects and type-I interferon (IFN) sensitivity of the variants remain poorly characterized. Here, we assessed B.1.1.7 and B.1.351 spread and fusion in cell cultures. B.1.1.7 and B.1.351 replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells and were similarly sensitive to IFN. The variants formed larger and more numerous syncytia. Variant Spikes, in the absence of any other viral proteins, resulted in faster fusion relative to D614G. B.1.1.7 and B.1.351 fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in the variant Spikes modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. Also, B.1.1.7 and B.1.351 variants remain sensitive to innate immunity components. The mutations present in the two variants globally enhance viral fusogenicity and allow for antibody evasion.

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