scholarly journals Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

2020 ◽  
Author(s):  
David Olagnier ◽  
Ensieh Farahani ◽  
Jacob Thyrsted ◽  
Julia B. Cadanet ◽  
Angela Herengt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Dimethyl Fumarate ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Independent Mechanism ◽  
Pathogenic Viruses ◽  
Anti Oxidant ◽  
Simplex Virus

AbstractAntiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

scholarly journals Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

2020 ◽  
Author(s):  
David P. Olagnier ◽  
Ensieh Farahani ◽  
Jacob Thyrsted ◽  
Julia B. Cadanet ◽  
Angela Herengt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Dimethyl Fumarate ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Independent Mechanism ◽  
Pathogenic Viruses ◽  
Anti Oxidant ◽  
Simplex Virus

Abstract Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a potent cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence Summary: NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

scholarly journals SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
David Olagnier ◽  
Ensieh Farahani ◽  
Jacob Thyrsted ◽  
Julia Blay-Cadanet ◽  
Angela Herengt ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Type I Interferon ◽  
Dimethyl Fumarate ◽  
Inhibitory Effect ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Independent Mechanism ◽  
Pathogenic Viruses ◽  
Antioxidant Gene Expression ◽  
Simplex Virus

Abstract Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.

scholarly journals Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

Virology ◽  
2008 ◽  
Vol 374 (2) ◽  
pp. 487-494 ◽  
Author(s):  
Karen E. Johnson ◽  
Byeongwoon Song ◽  
David M. Knipe
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus

scholarly journals Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Maxime Chapon ◽  
Kislay Parvatiyar ◽  
Saba Roghiyh Aliyari ◽  
Jeffrey S. Zhao ◽  
Genhong Cheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Throughput ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Interferon Response ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. IMPORTANCE This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.

scholarly journals Herpes Simplex Virus Type 1 Infection Disturbs the Mitochondrial Network, Leading to Type I Interferon Production through the RNA Polymerase III/RIG-I Pathway

mBio ◽  
2021 ◽  
Author(s):  
Noémie Berry ◽  
Rodolphe Suspène ◽  
Vincent Caval ◽  
Pierre Khalfi ◽  
Guillaume Beauclair ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Type I Interferon ◽  
Rna Polymerase Iii ◽  
Type I ◽  
Interferon Production ◽  
Mitochondrial Network ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus

Herpes simplex virus 1 (HSV-1) impairs the mitochondrial network through the viral protein UL12.5. This leads to the fusion of mitochondria and simultaneous release of mitochondrial DNA (mtDNA) in a mouse model.

scholarly journals Suppression of PACT-Induced Type I Interferon Production by Herpes Simplex Virus 1 Us11 Protein

2013 ◽  
Vol 87 (24) ◽  
pp. 13141-13149 ◽  
Author(s):  
C. Kew ◽  
P.-Y. Lui ◽  
C.-P. Chan ◽  
X. Liu ◽  
S. W. N. Au ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Us11 Protein

scholarly journals The γ134.5 Protein of Herpes Simplex Virus 1 Is Required To Interfere with Dendritic Cell Maturation during Productive Infection

2009 ◽  
Vol 83 (10) ◽  
pp. 4984-4994 ◽  
Author(s):  
Huali Jin ◽  
Yijie Ma ◽  
Bellur S. Prabhakar ◽  
Zongdi Feng ◽  
Tibor Valyi-Nagy ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Wild Type Virus ◽  
Type I ◽  
Interferon Production ◽  
Type Virus ◽  
Null Mutant ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Mhc Ii ◽  
Simplex Virus

ABSTRACT The γ134.5 protein of herpes simplex virus 1 is an essential factor for viral virulence. In infected cells, this viral protein prevents the translation arrest mediated by double-stranded RNA-dependent protein kinase R. Additionally, it associates with and inhibits TANK-binding kinase 1, an essential component of Toll-like receptor-dependent and -independent pathways that activate interferon regulatory factor 3 and cytokine expression. Here, we show that γ134.5 is required to block the maturation of conventional dendritic cells (DCs) that initiate adaptive immune responses. Unlike wild-type virus, the γ134.5 null mutant stimulates the expression of CD86, major histocompatibility complex class II (MHC-II), and cytokines such as alpha/beta interferon in immature DCs. Viral replication in DCs inversely correlates with interferon production. These phenotypes are also mirrored in a mouse ocular infection model. Further, DCs infected with the γ134.5 null mutant effectively activate naïve T cells whereas DCs infected with wild-type virus fail to do so. Type I interferon-neutralizing antibodies partially reverse virus-induced upregulation of CD86 and MHC-II, suggesting that γ134.5 acts through interferon-dependent and -independent mechanisms. These data indicate that γ134.5 is involved in the impairment of innate immunity by inhibiting both type I interferon production and DC maturation, leading to defective T-cell activation.

Sign in / Sign up

Export Citation Format

Share Document