Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication

Ming

et al. 2020

PLoS Pathog

Self Cite

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.

Section: Plos Pathogensmentioning

confidence: 99%

“…PRV-GFP, PRV-QXX and PRRSV-BJ4 were used as previously described [57,72,74]. VSV-GFP, NDV-GFP and H1N1-PR8 were gifts from Yong-Tao Li (Henan Agricultural University, China) [75].…”

Section: Cells and Virusesmentioning

confidence: 99%

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

Ming

et al. 2020

PLoS Pathog

Self Cite

“…Upon activation by the innate immune pathways, IFNs bind to cell surface receptors and initiate a signaling cascade through the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway, leading to the transcriptional regulation of hundreds of IFN-stimulated genes (ISGs) that are highly effective at resisting and controlling pathogens [10,11]. We previously found that porcine cholesterol 25-hydroxylase (CH25H) is an ISG induced by either IFN or PRV infection [12]. CH25H catalyzes 25hydroxycholesterol production to inhibit PRV entry.…”

Section: Introductionmentioning

confidence: 99%

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

International Journal of Biological Macromolecules

Ming

et al. 2020

Self Cite

a b s t r a c tKeywords: PRV IFITMs GAS/STING/TBK1/IRF3 innate immune pathway Viral entry Interferon-inducible transmembrane proteins (IFITMs) restrict infection by several viruses, such as influenza A virus, West Nile virus and dengue virus. It has not been determined whether porcine IFITMs (pIFITMs) inhibit infection by pseudorabies virus (PRV), an enveloped, double-stranded DNA virus, which is the etiological agent of Aujeszky's disease in pigs. Here, we report that PRV infection elicited pIFITM1 expression in PK15 porcine kidney epithelial cells and 3D4/21 alveolar macrophages. pIFITM2 and pIFITM3 expression was only elevated in PK15 cells during PRV infection. Depletion of pIFITM1 using RNA interference, either in PK15 or in 3D4/21 cells, enhanced PRV infection while overexpression of pIFITM1 had the opposite effect. Knockdown of pIFITM2 and pIFITM3 did not influence PRV infection, suggesting that pIFITM2 and pIFITM3 are independent of PRV infection. PRV-induced pIFITM1 expression was dependent on the cGAS/STING/TBK1/IRF3 innate immune pathway and interferon-alpha receptor-1, suggesting that pIFITM1 is up-regulated by the type I interferon signaling pathway. The anti-PRV role of pIFITM1 was inhibited upon PRV entry. Our data demonstrate that pIFITM1 is a host restriction factor that inhibits PRV entry that may shed light on a strategy for prevention of PRV infection.

“…A number of studies have illustrated that CH25H can be upregulated by some viruses, including HCV, PRRSV, and PRV (Anggakusuma et al, 2015;Song et al, 2017;Wang et al, 2017). In the present study, we investigated whether PEDV infection could upregulate CH25H expression in Vero cells.…”

Section: Pedv Infection Downregulates Ch25h Expression and Ch25h Is mentioning

confidence: 90%

“…At present, many anti-PEDV therapies are in general use, including recombinant Lactobacillus casei expressing dendritic cell-targeting peptide fused with the COE protein of PEDV (Langel et al, 2016), and IFNlambda, which preferably inhibits PEDV infection (Li et al, 2017b). Previous studies revealed that CH25H can be induced by several viruses, including HCV, PRRSV, and PRV (Anggakusuma et al, 2015;Song et al, 2017;Wang et al, 2017). In contrast, the present study demonstrates that CH25H expression can be downregulated by PEDV infection, and CH25H cannot be induced by IFN-α in Vero cells.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol 25-hydroxylase negatively regulates porcine intestinal coronavirus replication by the production of 25-hydroxycholesterol

Zhang

Song

Veterinary Microbiology

et al. 2019

Cholesterol 25-hydroxylase Porcine epidemic diarrhea virus 25-hydroxycholesterol Porcine transmissible gastroenteritis virus A B S T R A C TCholesterol 25-hydroxylase (CH25H) has been shown lately to be a host restriction factor that encodes an enzyme, which catalyzes the oxidized form of cholesterol to 25-hydroxycholesterol (25HC). A series of studies have shown that 25HC activity in hosts plays a vital role in inhibiting viral infection. In this study, we explored the antiviral effect of CH25H and 25HC on porcine epidemic diarrhea virus (PEDV), which causes high mortality rates in newborn piglets with severe diarrhea, and considerable financial loss in the swine industry worldwide. Our results showed that PEDV infection downregulated the expression of CH25H in Vero cells. An overexpression and knockdown assay indicated that CH25H has significant antiviral action against PEDV, and a CH25H mutant (CH25H-M) that lacks hydroxylase activity also retains antiviral activity to a lesser extent. Furthermore, 25HC had a broad-spectrum antiviral effect against different PEDV strains by blocking viral entry. In addition, CH25H and 25HC inhibited the replication of porcine transmissible gastroenteritis virus (TGEV). Taken together, CH25H as a natural host restriction factor could inhibit PEDV and TGEV infection.