scholarly journals The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Yueyan Liao ◽  
Xiangyu Ke ◽  
Tianyi Deng ◽  
Qingsong Qin
Keyword(s):  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Nuclear Export ◽  
Second Generation ◽  
Type I Interferon ◽  
Opportunistic Pathogen ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Hcmv Replication

Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.

scholarly journals The Tiers and Dimensions of Evasion of the Type I Interferon Response by Human Cytomegalovirus

2013 ◽  
Vol 425 (24) ◽  
pp. 4857-4871 ◽  
Author(s):  
Lisi Amsler ◽  
Marieke C. Verweij ◽  
Victor R. DeFilippis
Keyword(s):  
Human Cytomegalovirus ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I

scholarly journals Human Cytomegalovirus UL23 Attenuates Signal Transducer and Activator of Transcription 1 Phosphorylation and Type I Interferon Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Linyuan Feng ◽  
Wanwei Li ◽  
Xingyuan Wu ◽  
Xiaotian Li ◽  
Xiaoping Yang ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Type I Interferon ◽  
Signal Transduction Pathway ◽  
Interferon Response ◽  
Type I ◽  
Signal Transducer ◽  
Tyrosine Kinase 2 ◽  
Disease Occurrence ◽  
Key Factor ◽  
Determining Factor

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

scholarly journals Bud13 Promotes a Type I Interferon Response by Countering Intron Retention in Irf7

2018 ◽  
Author(s):  
Luke S. Frankiw ◽  
Devdoot Majumdar ◽  
Christian Burns ◽  
Annie Moradian ◽  
Michael J. Sweredoski ◽  
...  
Keyword(s):  
Rna Binding ◽  
Type I Interferon ◽  
Intron Retention ◽  
Global Analysis ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Gene Expression Control

SUMMARYIntron retention (IR) has emerged as an important mechanism of gene expression control. Despite this, the factors that control IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified Bud13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in Bud13 led to increased IR, decreased mature Irf7 transcript and protein levels, and consequently to a dampened type I interferon response. This impairment of Irf7 production in Bud13-deficient cells compromised their ability to withstand VSV infection. Global analysis of Bud13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a Bud13-dependent manner. Deficiency of Bud13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, Bud13 facilitates the expression of genes at which IR occurs.

scholarly journals Suppression of Type I Interferon Signaling by E1A via RuvBL1/Pontin

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Oladunni Olanubi ◽  
Jasmine Rae Frost ◽  
Sandi Radko ◽  
Peter Pelka
Keyword(s):  
Gene Expression ◽  
Cellular Response ◽  
Type I Interferon ◽  
Early Gene ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Interferon Signaling ◽  
Interferon Pathway ◽  
Regulated Promoters

ABSTRACT Suppression of interferon signaling is of paramount importance to a virus. Interferon signaling significantly reduces or halts the ability of a virus to replicate; therefore, viruses have evolved sophisticated mechanisms that suppress activation of the interferon pathway or responsiveness of the infected cell to interferon. Adenovirus has multiple modes of inhibiting the cellular response to interferon. Here, we report that E1A, previously shown to regulate interferon signaling in multiple ways, inhibits interferon-stimulated gene expression by modulating RuvBL1 function. RuvBL1 was previously shown to affect type I interferon signaling. E1A binds to RuvBL1 and is recruited to RuvBL1-regulated promoters in an interferon-dependent manner, preventing their activation. Depletion of RuvBL1 impairs adenovirus growth but does not appear to significantly affect viral protein expression. Although RuvBL1 has been shown to play a role in cell growth, its depletion had no effect on the ability of the virus to replicate its genome or to drive cells into S phase. E1A was found to bind to RuvBL1 via the C terminus of E1A, and this interaction was important for suppression of interferon-stimulated gene transcriptional activation and recruitment of E1A to interferon-regulated promoters. Here, we report the identification of RuvBL1 as a new target for adenovirus in its quest to suppress the interferon response. IMPORTANCE For most viruses, suppression of the interferon signaling pathway is crucial to ensure a successful replicative cycle. Human adenovirus has evolved several different mechanisms that prevent activation of interferon or the ability of the cell to respond to interferon. The viral immediate-early gene E1A was previously shown to affect interferon signaling in several different ways. Here, we report a novel mechanism reliant on RuvBL1 that E1A uses to prevent activation of interferon-stimulated gene expression following infection or interferon treatment. This adds to the growing knowledge of how viruses are able to inhibit interferon and identifies a novel target used by adenovirus for modulation of the cellular interferon pathway.

scholarly journals IMMU-22. EARLY RELEASE OF TYPE I INTERFERON DRIVES BRAIN CANCER IMMUNOGENICITY AND RESPONSE TO IMMUNOTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii109-ii109
Author(s):  
Brandon Wummer ◽  
Sadeem Qdaisat ◽  
Adam Grippin ◽  
Aida Karachi ◽  
Frances Weidert ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Cancer ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Tumor Models ◽  
Early Release ◽  
M1 Macrophage ◽  
The Brain

Abstract BACKGROUND Molecular drivers of cancer immunogenicity in brain tumors are still being unraveled. While BATF3 expression, STING, and interferon response factors (IRFs) are necessary for cancer immunogenicity, the presence of type I interferon (IFN-I) is contextual having been reported to elicit both anti-tumoral and pro-tumoral effects. A better understanding of IFN-I signaling mechanisms is necessary to elucidate drivers of brain cancer immunogenicity and resistance. OBJECTIVE We sought to assess the role of IFN-I signaling in brain tumor immunogenicity and response to immune checkpoint inhibitors (ICIs) in ICI sensitive brain tumor models (i.e. GL261). We then sought to develop strategies to reset IFN-I signaling in ICI resistant brain tumor models (i.e. KR158b). METHODS To reset IFN-I signaling in immunologically ‘cold’ tumors unresponsive to ICIs, we developed lipid-nanoparticles (NPs) to deliver mRNA payloads to the brain tumor microenvironment (TME). RESULTS In immune-sensitive GL261 tumors, we showed that early release of IFN-I unlocks cancer immunogenicity and ICI response. Blockade of IFN-I during tumorigenesis (within 24h, but not days later) increases tumorigenicity and abrogates ICI activity in sensitive tumors. In ICI resistant KR158b tumors, we show that systemic administration of tumor-derived RNA-NPs localize to myeloid cells within the TME for simultaneous activation of multiple innate pathways including BATF3 (necessary for effector DCs), IRF5 (necessary for M2 to M1 macrophage reprograming), and IRF7 (necessary for IFN-I production). These RNA-NPs induce near-immediate release of IFN-I (within hours), reprogram the brain TME in an IFNAR1 (IFN-I receptor) dependent manner, and elicit significant anti-KR158b efficacy as a monotherapy. Following IFNAR1 blockade, RNA-NP mediated anti-tumor efficacy was abrogated. We demonstrated safety of tumor-specific RNA-NPs (derived from KR158b) in acute/chronic GLP toxicity studies without normal-brain cross-reactivity, and confirmed feasibility/safety and immunologic activity in large-animal studies. FUTURE DIRECTIONS We have since received FDA-IND approval for first-in-human trials (IND#BB-19304) in glioblastoma patients.

scholarly journals Porcine Epidemic Diarrhea Virus Infection Inhibits Interferon Signaling by Targeted Degradation of STAT1

2016 ◽  
Vol 90 (18) ◽  
pp. 8281-8292 ◽  
Author(s):  
Longjun Guo ◽  
Xiaolei Luo ◽  
Ren Li ◽  
Yunfei Xu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Porcine Epidemic Diarrhea Virus ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Infection Type ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

ABSTRACTPorcine epidemic diarrhea virus (PEDV) is a worldwide-distributed alphacoronavirus, but the pathogenesis of PEDV infection is not fully characterized. During virus infection, type I interferon (IFN) is a key mediator of innate antiviral responses. Most coronaviruses develop some strategy for at least partially circumventing the IFN response by limiting the production of IFN and by delaying the activation of the IFN response. However, the molecular mechanisms by which PEDV antagonizes the antiviral effects of interferon have not been fully characterized. Especially, how PEDV impacts IFN signaling components has yet to be elucidated. In this study, we observed that PEDV was relatively resistant to treatment with type I IFN. Western blot analysis showed that STAT1 expression was markedly reduced in PEDV-infected cells and that this reduction was not due to inhibition of STAT1 transcription. STAT1 downregulation was blocked by a proteasome inhibitor but not by an autophagy inhibitor, strongly implicating the ubiquitin-proteasome targeting degradation system. Since PEDV infection-induced STAT1 degradation was evident in cells pretreated with the general tyrosine kinase inhibitor, we conclude that STAT1 degradation is independent of the IFN signaling pathway. Furthermore, we report that PEDV-induced STAT1 degradation inhibits IFN-α signal transduction pathways. Pharmacological inhibition of STAT1 degradation rescued the ability of the host to suppress virus replication. Collectively, these data show that PEDV is capable of subverting the type I interferon response by inducing STAT1 degradation.IMPORTANCEIn this study, we show that PEDV is resistant to the antiviral effect of IFN. The molecular mechanism is the degradation of STAT1 by PEDV infection in a proteasome-dependent manner. This PEDV infection-induced STAT1 degradation contributes to PEDV replication. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response.

scholarly journals Abrogation of the Interferon Response Promotes More Efficient Human Cytomegalovirus Replication

2014 ◽  
Vol 89 (2) ◽  
pp. 1479-1483 ◽  
Author(s):  
Brian P. McSharry ◽  
Simone K. Forbes ◽  
Selmir Avdic ◽  
Richard E. Randall ◽  
Gavin W. G. Wilkinson ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Vital Role ◽  
Human Cells ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifns ◽  
Hcmv Replication ◽  
Primary Human Cells

The effect of abrogating the interferon (IFN) response on human cytomegalovirus (HCMV) replication was investigated using primary human cells engineered to block either the production of or the response to type I IFNs. In IFN-deficient cells, HCMV produced larger plaques and spread and replicated more rapidly than in parental cells. These cells demonstrate the vital role of IFNs in controlling HCMV replication and provide useful tools to investigate the IFN response to HCMV.

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