Broadly Antiviral Activities of TAP1 through Activating the TBK1-IRF3-Mediated Type I Interferon Production

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune signaling is not yet fully understood. In the present study, we reported that TAP1, as a product of interferon-stimulated genes (ISGs), had broadly antiviral activity against various viruses such as herpes simplex virus 1 (HSV-1), adenoviruses (AdV), vesicular stomatitis virus (VSV), dengue virus (DENV), Zika virus (ZIKV), and influenza virus (PR8) etc. This antiviral activity by TAP1 was further confirmed by series of loss-of-function and gain-of-function experiments. Our further investigation revealed that TAP1 significantly promoted the interferon (IFN)-β production through activating the TANK binding kinase-1 (TBK1) and the interferon regulatory factor 3 (IRF3) signaling transduction. Our work highlighted the broadly anti-viral function of TAP1 by modulating innate immunity, which is independent of its well-known function of antigen presentation. This study will provide insights into developing novel vaccination and immunotherapy strategies against emerging infectious diseases.

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Uncontrolled herpes simplex virus-1 replication due to type I IFN receptor deficiency results in selective destruction of lymphatic vessels and inhibition of antigen presentation

Cytokine ◽

10.1016/j.cyto.2009.07.141 ◽

2009 ◽

Vol 48 (1-2) ◽

pp. 50

Author(s):

Todd R. Wuest ◽

Daniel J.J. Carr

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Antigen Presentation ◽

Lymphatic Vessels ◽

Type I ◽

Type I Ifn ◽

Herpes Simplex Virus 1 ◽

Selective Destruction ◽

Simplex Virus

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HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections

Journal of Experimental Medicine ◽

10.1084/jem.20161630 ◽

2017 ◽

Vol 214 (11) ◽

pp. 3263-3277 ◽

Cited By ~ 12

Author(s):

Lei Sun ◽

Zhengfan Jiang ◽

Victoria A. Acosta-Rodriguez ◽

Michael Berger ◽

Xin Du ◽

...

Keyword(s):

Viral Infections ◽

Poly I:C ◽

Type I ◽

Induced Mutations ◽

Herpes Simplex Virus 1 ◽

Double Stranded Rna ◽

Polycytidylic Acid ◽

Interferon Regulatory Factor 1 ◽

Mouse Macrophages ◽

Simplex Virus

Transcriptional regulation of numerous interferon-regulated genes, including Toll-like receptor 3 (Tlr3), which encodes an innate immune sensor of viral double-stranded RNA, depends on the interferon regulatory factor 1 (IRF1) and IRF2 transcription factors. We detected specific abrogation of macrophage responses to polyinosinic-polycytidylic acid (poly(I:C)) resulting from three independent N-ethyl-N-nitrosourea–induced mutations in host cell factor C2 (Hcfc2). Hcfc2 mutations compromised survival during influenza virus and herpes simplex virus 1 infections. HCFC2 promoted the binding of IRF1 and IRF2 to the Tlr3 promoter, without which inflammatory cytokine and type I IFN responses to the double-stranded RNA analogue poly(I:C) are reduced in mouse macrophages. HCFC2 was also necessary for the transcription of a large subset of other IRF2-dependent interferon-regulated genes. Deleterious mutations of Hcfc2 may therefore increase susceptibility to diverse infectious diseases.

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Faculty Opinions recommendation of Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1255961.723060 ◽

2009 ◽

Author(s):

D Scott Schmid ◽

Jennifer Folster

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Type I Interferon ◽

Type I ◽

Herpes Simplex Virus 1 ◽

Simplex Virus

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Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

Scientific Reports ◽

10.1038/s41598-020-77725-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

David Shahnazaryan ◽

Rana Khalil ◽

Claire Wynne ◽

Caroline A. Jefferies ◽

Joan Ní Gabhann-Dromgoole ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Immune Responses ◽

Tear Film ◽

Cell Protein ◽

Type I ◽

Type I Ifn ◽

Herpes Simplex Virus 1 ◽

Simplex Virus ◽

Hsv 1

AbstractHerpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.

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Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽

10.3390/v13020196 ◽

2021 ◽

Vol 13 (2) ◽

pp. 196

Author(s):

Sara Artusi ◽

Emanuela Ruggiero ◽

Matteo Nadai ◽

Beatrice Tosoni ◽

Rosalba Perrone ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Dna Replication ◽

Herpes Simplex ◽

Antiviral Activity ◽

Herpes Simplex Virus 1 ◽

Tem Analysis ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

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Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Journal of Experimental Medicine ◽

10.1084/jem.20142274 ◽

2015 ◽

Vol 212 (9) ◽

pp. 1371-1379 ◽

Cited By ~ 98

Author(s):

Line Lykke Andersen ◽

Nanna Mørk ◽

Line S. Reinert ◽

Emil Kofod-Olsen ◽

Ryo Narita ◽

...

Keyword(s):

Herpes Simplex ◽

Autosomal Dominant ◽

Viral Infections ◽

Herpes Simplex Encephalitis ◽

Type I ◽

Toll Like Receptor ◽

Loss Of Function ◽

Impaired Ability ◽

Increased Susceptibility ◽

Hsv 1

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans.

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Identification of Feline Interferon Regulatory Factor 1 as an Efficient Antiviral Factor against the Replication of Feline Calicivirus and Other Feline Viruses

BioMed Research International ◽

10.1155/2018/2739830 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Yongxiang Liu ◽

Xiaoxiao Liu ◽

Hongtao Kang ◽

Xiaoliang Hu ◽

Jiasen Liu ◽

...

Keyword(s):

Antiviral Activity ◽

Viral Infections ◽

Interferon Regulatory Factor ◽

Feline Calicivirus ◽

Type I ◽

Norwalk Virus ◽

Regulatory Factor ◽

Feline Panleukopenia Virus ◽

Protein Levels ◽

Interferon Regulatory Factor 1

Interferons (IFNs) can inhibit most, if not all, viral infections by eliciting the transcription of hundreds of interferon-stimulated genes (ISGs). Feline calicivirus (FCV) is a highly contagious pathogen of cats and a surrogate for Norwalk virus. Interferon efficiently inhibits the replication of FCV, but the mechanism of the antiviral activity is poorly understood. Here, we evaluated the anti-FCV activity of ten ISGs, whose antiviral activities were previously reported. The results showed that interferon regulatory factor 1 (IRF1) can significantly inhibit the replication of FCV, whereas the other ISGs tested in this study failed. Further, we found that IRF1 was localized in the nucleus and efficiently activated IFN-β and the ISRE promoter. IRF1 can trigger the production of endogenous interferon and the expression of ISGs, suggesting that IRF1 can positively regulate IFN signalling. Importantly, the mRNA and protein levels of IRF1 were reduced upon FCV infection, which may be a new strategy for FCV to evade the innate immune system. Finally, the antiviral activity of IRF1 against feline panleukopenia virus, feline herpesvirus, and feline infectious peritonitis virus was demonstrated. These data indicate that feline IRF1 plays an important role in regulating the host type I IFN response and inhibiting feline viral infections.

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