Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Gao, Li; Li, Kai; Zhang, Yu; Liu, Yongzhen; Liu, Changjun; Zhang, Yanping; Gao, Yulong; Qi, Xiaole; Cui, Hongyu; Wang, Yongqiang; Wang, Xiaomei

doi:10.1128/jvi.01934-18

Cited by 41 publications

(42 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the later time points of infection, the titer of the CHa strain was significantly lower than that of the CHv strain (Figure 5). In the previous studies on DPV and MDV viruses, researchers observed the slight up-regulation of the innate immune molecules around 6 hpi in the fibroblasts, and the rapid down-regulation of these molecules from 12 hpi (23,52). These results are consistent with the data we obtained in this study; we hypothesized that DPV virulent strains have multiple, highly potent proteins that inhibit innate immunity, and the mechanism of suppressing innate immunity will be further studied in the future.…”

Section: Discussionsupporting

confidence: 92%

Isolation and Selection of Duck Primary Cells as Pathogenic and Innate Immunologic Cell Models for Duck Plague Virus

Tian

Cai

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Duck plague virus (DPV) is a representative pathogen transmitted among aquatic animals that causes gross lesions and immune inhibition in geese and ducks. The mechanism of organ tropism and innate immune evasion of DPV has not been completely deciphered due to a lack of cell models to study the innate immune manipulation and pathogenicity of aquatic viruses. In the present study, we isolated five types of duck primary cells [duck embryo fibroblasts (DEFs), neurons, astrocytes, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages] to identify appropriate cell models for DPV, using tropism infection and innate immunologic assays. Cells responded differently to stimulation with DNA viruses or RNA virus analogs. DPV infection exhibited broad tropism, as the recombinant virulent strain (CHv-GFP) infected DEFs, neurons, astrocytes, and monocytes/macrophages, but not the PBMCs, as the expression of EGFP was negligible. The basal levels of innate immunity molecules were highest in monocytes/macrophages and lower in DEFs and astrocytes. Conversely, the titer and genomic copy number of the attenuated virus strain was higher in DEFs and astrocytes than in neurons and monocytes/macrophages. The titer and genomic copy number of the attenuated virus strain were higher compared with the virulent strain in DEFs, neurons, and astrocytes. The innate immune response was not significantly induced by either DPV strain in DEFs, neurons, or astrocytes. The virulent strain persistently infected monocytes/macrophages, but the attenuated strain did so abortively, and this was accompanied by the phenomenon of innate immune inhibition and activation by the virulent and attenuated strains, respectively. Blockage of IFNAR signaling promoted replication of the attenuated strain. Pre-activation of IFNAR signaling inhibited infection by the virulent strain. The selection assay results indicated that induction of innate immunity plays an essential role in controlling DPV infection, and monocytes/macrophages are an Tian et al.Duck Primary Cells Infection Models important cell model for further investigations. Our study provided practical methods for isolating and culturing duck primary cells, and our results will facilitate further investigations of organ tropism, innate immune responses, latent infection, and the effectiveness of antiviral drugs for treating DPV and potentially other aerial bird pathogens.

show abstract

Section: Discussionsupporting

confidence: 92%

Isolation and Selection of Duck Primary Cells as Pathogenic and Innate Immunologic Cell Models for Duck Plague Virus

Tian

Cai

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…The strategies were suggested to be especially important for MDV, because periodic lytic replication and de novo infection occur naturally and are required for long-term persistence and pathogenesis in its hosts. We recently reported that the cGAS-STING pathway mediates the IFN-␤ responses to MDV in chicken fibroblasts and macrophages, and the VP23 protein encoded by MDV inhibited this pathway by suppressing IRF7 activation (32). In the present study, based on a screen of MDV open reading frames (ORFs), we identified MDV RLORF4 as a novel efficient inhibitor of IFN-␤ induction.…”

Section: Discussionmentioning

confidence: 73%

“…DF-1, a chicken fibroblast cell line, is known to respond to foreign DNA such as interferon-stimulatory DNA (ISD) and poly(dA•dT) (31). The IFN-␤ promoter was highly activated by cotransfecting the same amounts of cGAS and STING expression plasmids in DF-1 cells (32). With this model, we screened MDV proteins that could antagonize IFN-␤ production mediated by cGAS-STING and identified RLORF4 as one candidate.…”

Section: Resultsmentioning

confidence: 99%

Marek’s Disease Virus RLORF4 Inhibits Type I Interferon Production by Antagonizing NF-κB Activation

Liu

Gao

et al. 2019

J Virol

Self Cite

View full text Add to dashboard Cite

Marek’s disease virus (MDV), which causes T cell lymphomas in chickens, is economically important and has contributed to knowledge of herpesvirus-associated oncogenicity. The DNA-sensing pathway induces innate immune responses against DNA virus infection, and nuclear factor κB (NF-κB) signaling is critical for the establishment of innate immunity. Here, we report that RLORF4, an MDV-specific protein directly involved in viral attenuation, is an inhibitor of the DNA-sensing pathway. The results showed that ectopically expressed RLORF4 blocked beta interferon (IFN-β) promoter activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). RLORF4 selectively inhibited the activation of NF-κB but not IFN-regulatory factor 7. RLORF4 was found to bind the endogenous NF-κB subunits p65 and p50, and it also bound to the Rel homology domains of these subunits. Furthermore, RLORF4 suppressed the nuclear translocation of p65 and p50 mediated by tumor necrosis factor alpha and interferon-stimulatory DNA. Finally, deletion of RLORF4 from the MDV genome promoted IFN-β and interleukin-6 (IL-6) production in vitro and in vivo. In the absence of RLORF4, the host cellular immunity was significantly increased, and reduced viral titers were observed during infection of chickens. Our results suggest that the RLORF4-mediated suppression of the host antiviral innate immunity might play an important role in MDV pathogenesis. IMPORTANCE Marek’s disease virus (MDV) RLORF4 has been shown to be directly involved in the attenuation of MDV upon serial passages in vitro; however, the exact function of this protein during viral infection was not well characterized. This study demonstrated that RLORF4 significantly inhibits cGAS-STING-mediated NF-κB activation by binding to the Rel homology domains of the NF-κB subunits p65 and p50, interrupting their translocation to the nuclei and thereby inhibiting IFN-β production. Furthermore, RLORF4 deficiency promoted the induction of IFN-β and downstream IFN-stimulated genes during MDV infection in chickens. Our results suggest that the contribution of RLORF4 to MDV virulence may stem from its inhibition of viral DNA-triggered IFN-β responses.

show abstract

“…Another mammalian PRR that recognizes DNA in a sequence-independent manner is cGAS, resulting in type I IFN production in a STING-dependent manner. Although cGAS stimulation by DNA results in type I IFN production in chicken, CpG-ODN stimulation of TLR21 was found to up-regulate the expression of INF-γ, IL-10, and IL-12p40, but not IFN-α and IFN-β [50,174]. DNA stimulation of cGAS can be harnessed to enhance anti-viral type I IFN production upon vaccination against DNA or RNA viruses.…”

Section: Discussionmentioning

confidence: 97%

“…Like in mammalian, cGAS-STING-TBK1-IRF7 axis plays a critical role in restricting DNA virus infection in avian. However, an avian tumor virus known as Marek's disease virus has evolved interferon-antagonistic proteins such as VP23 and oncoprotein Meq which suppress DNA sensing pathways and downstream IRF7 activation [173,174].…”

Section: Cgasmentioning

confidence: 99%

Avian Pattern Recognition Receptor Sensing and Signaling

Neerukonda

Katneni

2020

Veterinary Sciences

View full text Add to dashboard Cite

Pattern recognition receptors (PRRs) are a class of immune sensors that play a critical role in detecting and responding to several conserved patterns of microorganisms. As such, they play a major role in the maintenance of immune homeostasis and anti-microbial defense. Fundamental knowledge pertaining to the discovery of PRR functions and their ligands continue to advance the understanding of immune system and disease resistance, which led to the rational design and/or application of various PRR ligands as vaccine adjuvants. In addition, the conserved nature of many PRRs throughout the animal kingdom has enabled the utilization of the comparative genomics approach in PRR identification and the study of evolution, structural features, and functions in many animal species including avian. In the present review, we focused on PRR sensing and signaling functions in the avian species, domestic chicken, mallard, and domestic goose. In addition to summarizing recent advances in the understanding of avian PRR functions, the present review utilized a comparative biology approach to identify additional PRRs, whose functions have been well studied in mammalians but await functional characterization in avian.

show abstract

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Cited by 41 publications

References 48 publications

Isolation and Selection of Duck Primary Cells as Pathogenic and Innate Immunologic Cell Models for Duck Plague Virus

Isolation and Selection of Duck Primary Cells as Pathogenic and Innate Immunologic Cell Models for Duck Plague Virus

Marek’s Disease Virus RLORF4 Inhibits Type I Interferon Production by Antagonizing NF-κB Activation

Avian Pattern Recognition Receptor Sensing and Signaling

Contact Info

Product

Resources

About