Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection

Wang, Jiang; Wang, Chunfeng; Ming, Sheng-Li; Li, Guoli; Zeng, Lei; Wang, Meng-Di; Su, Bing-Qian; Wang, Qi; Yang, Gangyi; Chu, Bei-Bei

doi:10.1016/j.ijbiomac.2019.10.162

Cited by 29 publications

(25 citation statements)

References 48 publications

(52 reference statements)

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“…All cells were grown in monolayers at 37°C under 5% CO 2 . PRV-QXX was used as previously described ( 34 ).…”

Section: Methodsmentioning

confidence: 99%

“…The sgRNA sequences were as follows: p65 -sgRNA1: 5′-GCGCTCAGCCGGCAGTATCC-3′; p65 -sgRNA2: 5′-GCTCTCGCCCGGGATACTGC-3′; Nlrp3 -sgRNA: 5′-GTGCAAGCTGGCTCGTTACC-3′; Asc -sgRNA: 5′-GAAGCTCGTCAACTACTACC-3′; and Caspase-1 -sgRNA: 5′-GAACGCTACAGTTATGGATA-3′. The sgRNA sequences for Sting , Tbk1 , Irf3 , and Ifnar1 were used as previously described ( 34 ).…”

Section: Methodsmentioning

confidence: 99%

“…Sting –/– , Tbk1 –/– , Irf3 –/– , and Ifnar1 –/– PK15 cells were used as previously described ( 34 ). Sting –/– and Ifnar1 –/– 3D4/21 cells were generated through the same procedure as Sting –/– and Ifnar1 –/– PK15 cells ( 34 ).…”

Section: Methodsmentioning

confidence: 99%

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The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

et al. 2020

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Pigs have anatomical and physiological characteristics comparable to those in humans and, therefore, are a favorable model for immune function research. Interferons (IFNs) and inflammasomes have essential roles in the innate immune system. Here, we report that G10, a human-specific agonist of stimulator of interferon genes (STING), activates both type I IFN and the canonical NLRP3 inflammasome in a STING-dependent manner in porcine cells. Without a priming signal, G10 alone transcriptionally stimulated Sp1-dependent p65 expression, thus triggering activation of the nuclear factor-κB (NF-κB) signaling pathway and thereby priming inflammasome activation. G10 was also found to induce potassium efflux- and NLRP3/ASC/Caspase-1-dependent secretion of IL-1β and IL-18. Pharmacological and genetic inhibition of NLRP3 inflammasomes increased G10-induced type I IFN expression, thereby preventing virus infection, suggesting negative regulation of the NLRP3 inflammasome in the IFN response in the context of STING-mediated innate immune activation. Overall, our findings reveal a new mechanism through which G10 activates the NLRP3 inflammasome in porcine cells and provide new insights into STING-mediated innate immunity in pigs compared with humans.

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“…All cells were grown in monolayers at 37°C under 5% CO 2 . PRV-QXX was used as previously described ( 34 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

et al. 2020

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“…For instance, a group of antiviral restriction factors, the IFN-inducible transmembrane proteins (IFITMs) have been shown to inhibit PRV replication in porcine kidney epithelial (PK-15) cells and porcine alveolar macrophages. Porcine IFTM1 specifically inhibited PRV entry in these cells [138]. Furthermore, a porcine IFN-stimulated ubiquitin-like protein (pISG15) efficiently inhibited PRV infection by reducing viral titers and increasing type I IFN expression in vitro [139].…”

Section: Why Prv-infected Swine Do Not Itchmentioning

confidence: 99%

The Neuropathic Itch Caused by Pseudorabies Virus

Laval

Enquist

2020

Pathogens

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Pseudorabies virus (PRV) is an alphaherpesvirus related to varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1). PRV is the causative agent of Aujeskzy’s disease in swine. PRV infects mucosal epithelium and the peripheral nervous system (PNS) of its host where it can establish a quiescent, latent infection. While the natural host of PRV is the swine, a broad spectrum of mammals, including rodents, cats, dogs, and cattle can be infected. Since the nineteenth century, PRV infection is known to cause a severe acute neuropathy, the so called “mad itch” in non-natural hosts, but surprisingly not in swine. In the past, most scientific efforts have been directed to eradicating PRV from pig farms by the use of effective marker vaccines, but little attention has been given to the processes leading to the mad itch. The main objective of this review is to provide state-of-the-art information on the mechanisms governing PRV-induced neuropathic itch in non-natural hosts. We highlight similarities and key differences in the pathogenesis of PRV infections between non-natural hosts and pigs that might explain their distinctive clinical outcomes. Current knowledge on the neurobiology and possible explanations for the unstoppable itch experienced by PRV-infected animals is also reviewed. We summarize recent findings concerning PRV-induced neuroinflammatory responses in mice and address the relevance of this animal model to study other alphaherpesvirus-induced neuropathies, such as those observed for VZV infection.

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“…All cells were cultured in DMEM (10566-016, GIBCO) supplemented with 10% FBS (10099141C, GIBCO), 100 units/mL penicillin and 100 μg/mL streptomycin sulfate (B540732, Sangon). African green monkey kidney (MARC-145) cells and cGAS -/-, STING -/-, TBK1 -/-, IRF3 -/-, IFNAR1 -/-PK15 cells were cultivated as previously described [72,73].…”

Section: Cells and Virusesmentioning

confidence: 99%

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Wang

Ming

et al. 2020

PLoS Pathog

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Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases. Author summaryBRD4 has been well investigated in tumorigenesis for its contribution to chromatin remodeling and gene transcription. BRD4 inhibitors are used as promising chemotherapeutic drugs for cancer therapy. Here, we show a unique mechanism through which BRD4 inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the cGAS-STING pathway, in both cell culture and an animal model. STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials. Our data identify BRD4 inhibitors as a potent therapy not only for viral infection but also for cancer immunotherapy. PLOS PATHOGENSPLOS Pathogens | https://doi.

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Porcine IFITM1 is a host restriction factor that inhibits pseudorabies virus infection

Cited by 29 publications

References 48 publications

The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

The Neuropathic Itch Caused by Pseudorabies Virus

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

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