African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway

Dodantenna, Niranjan; Ranathunga, Lakmal; Chathuranga, W. A. Gayan; Weerawardhana, Asela; Cha, Jiwon; Subasinghe, Ashan; Gamage, Nuwan; Haluwana, D. K.; Kim, Yongkwan; Jheong, WeonHwa; Poo, Haryoung; Lee, Jong-Soo

doi:10.1128/jvi.01022-22

Cited by 34 publications

(33 citation statements)

References 87 publications

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“…cGAS acts as a PRR and binds pathogenic DNA to trigger an innate immune response through the production of cGAMP, which activates the adaptor STING. The cGAS-STING pathway is involved in the type I interferon and ISGs responses against microbial infections such as chicken adenovirus 4 and Marek’s Disease Virus in fibroblasts ( 7 , 20 ). In addition to sensing microbial DNA, this pathway is also involved in the defense against RNA virus infections ( 28 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs

Lin

Zheng²,

Xiao³

et al. 2023

Front. Immunol.

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Cyclic GMP-AMP Synthase (cGAS) is a pivotal adaptor of the signaling pathways involving the pattern recognition receptors and plays an important role in apoptosis and immune regulation. The cGAS function in mammals has been investigated extensively; however, the function of duck cGAS (du-cGAS) in response to viral infections is still unclear. This study aimed to clone the mallard (Anas platyrhynchos) cGAS homolog to investigate the function of duck cGAS (du-cGAS) in host antiviral innate immunity. The results showed that the open reading frame (ORF) region of the du-cGAS gene was 1296 bp, encoding 432 amino acids (aa) and exhibiting similar functional domains with its chicken counterpart. Knockdown of the endogenous du-cGAS by specific sgRNA strongly increased the replication of DNA viruses, including duck adenovirus B2 (DAdV B2) and duck short beak and dwarfism syndrome virus (SBDSV). However, the knockout did not impair the replication of novel duck reovirus (NDRV), an RNA virus. Furthermore, the mRNA expressions of type I interferon (IFNs) and vital interferon-stimulated genes (ISGs) were remarkably reduced in the du-cGAS knockout DEF cell line. Inversely, du-cGAS overexpression greatly activated the transcription of IFN-α, IFN-β, and vital ISGs, and impaired the replication of DAdV B2, SBDSV, and NDRV in the DEF cell line. Importantly, we found that a deletion of 68 aa in the N terminus didn’t impair the antiviral function of du-cGAS. Overexpressing NTase Core, C-Domain (Mab21), or Zinc-Ribbon domain independently had no antiviral effects. Generally, these results reveal that du-cGAS is a vital component of the innate immune system of ducks, with a universal antiviral activity, and provides a useful strategy for the control of waterfowl viral diseases.

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Section: Discussionmentioning

confidence: 99%

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs

Lin

Zheng²,

Xiao³

et al. 2023

Front. Immunol.

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“…However, cGAMP is likely to be cleaved by viral nucleases, which certainly restricts the STING-dependent IFN-I production [ 39 , 40 ]. Indeed, ASFV-encoded pEP364R and pC129R, homologs to the nuclease, exhibit strong phosphodiesterase activity [ 41 ]. Either pEP364R or pC129R can selectively interact with cGAMP, specifically mediating the cleavage of cGAMP with their enzyme activity [ 41 ].…”

Section: Suppression Of Ifn-i Production and Ifn-induced Antiviral Re...mentioning

confidence: 99%

Antagonisms of ASFV towards Host Defense Mechanisms: Knowledge Gaps in Viral Immune Evasion and Pathogenesis

Zhu

Deng³

et al. 2023

Viruses

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African swine fever (ASF) causes high morbidity and mortality of both domestic pigs and wild boars and severely impacts the swine industry worldwide. ASF virus (ASFV), the etiologic agent of ASF epidemics, mainly infects myeloid cells in swine mononuclear phagocyte system (MPS), including blood-circulating monocytes, tissue-resident macrophages, and dendritic cells (DCs). Since their significant roles in bridging host innate and adaptive immunity, these cells provide ASFV with favorable targets to manipulate and block their antiviral activities, leading to immune escape and immunosuppression. To date, vaccines are still being regarded as the most promising measure to prevent and control ASF outbreaks. However, ASF vaccine development is delayed and limited by existing knowledge gaps in viral immune evasion, pathogenesis, etc. Recent studies have revealed that ASFV can employ diverse strategies to interrupt the host defense mechanisms via abundant self-encoded proteins. Thus, this review mainly focuses on the antagonisms of ASFV-encoded proteins towards IFN-I production, IFN-induced antiviral response, NLRP3 inflammasome activation, and GSDMD-mediated pyroptosis. Additionally, we also make a brief discussion concerning the potential challenges in future development of ASF vaccine.

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“…They can interact with and cleave cGAMP in a phosphodiesterase activity-dependent manner, thus subverting cGAMP-mediated IFN signaling. Moreover, EP364R competitively combines with cGAMP, leading to the blockage of the interaction between cGAMP and STING, further enhancing its ability to antagonize the host antiviral innate immune response [ 54 ]. I226R can impair antiviral responses through the suppression of NF-κB and IRF3 activation.…”

Section: Asfv Regulation Of Innate Immune Responsementioning

confidence: 99%

Modulation of Host Antiviral Innate Immunity by African Swine Fever Virus: A Review

Yuan²,

Ma³

et al. 2022

Animals

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African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly contagious and fatal disease found in swine. However, the viral proteins and mechanisms responsible for immune evasion are poorly understood, which has severely hindered the development of vaccines. This review mainly focuses on studies involving the innate antiviral immune response of the host and summarizes the latest studies on ASFV genes involved in interferon (IFN) signaling and inflammatory responses. We analyzed the effects of candidate viral proteins on ASFV infection, replication and pathogenicity and identified potential molecular targets for novel ASFV vaccines. These efforts will contribute to the construction of novel vaccines and wonder therapeutics for ASF.

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African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway

Abstract: African swine fever (ASF) is a highly contagious hemorrhagic disease in domestic pigs and wild boars caused by African swine fever virus (ASFV). ASF is a deadly epidemic disease in the global pig industry, but no drugs or vaccines are available.

Cited by 34 publications

References 87 publications

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs

Duck cGAS inhibits DNA and RNA virus replication by activating IFNs and antiviral ISGs

Antagonisms of ASFV towards Host Defense Mechanisms: Knowledge Gaps in Viral Immune Evasion and Pathogenesis

Modulation of Host Antiviral Innate Immunity by African Swine Fever Virus: A Review

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