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African Swine Fever Virus CD2v Protein Induces β-Interferon Expression and Apoptosis in Swine Peripheral Blood Mononuclear Cells.

ABSTRACT: African swine fever (ASF) is a hemorrhagic disease of swine characterized by massive lymphocyte depletion in lymphoid tissues due to the apoptosis of B and T cells, a process likely triggered by factors released or secreted by infected macrophages. ASFV CD2v (EP402R) has been implicated in viral virulence and immunomodulation in vitro; however, its actual function(s) remains unknown. We found that CD2v expression in swine PK15 cells induces NF-κB-dependent IFN-β and ISGs transcription and an antiviral state. Similar results were observed for CD2v protein treated swine PBMCs and macrophages, the major ASFV target cell. Notably, treatment of swine PBMCs and macrophages with CD2v protein induced apoptosis. Immunoprecipitation and colocalization studies revealed that CD2v interacts with CD58, the natural host CD2 ligand. Additionally, CD58 knockdown in cells or treatment of cells with an NF-κB inhibitor significantly reduced CD2v-mediated NF-κB activation and IFN-β induction. Further, antibodies directed against CD2v inhibited CD2v-induced NF-κB activation and IFN-β transcription in cells. Overall, results indicate that ASFV CD2v activates NF-κB, which induces IFN signaling and apoptosis in swine lymphocytes/macrophages. We propose that CD2v released from infected macrophages may be a significant factor in lymphocyte apoptosis observed in lymphoid tissue during ASFV infection in pigs.

SUBMITTER: Chaulagain S

PROVIDER: S-EPMC8402892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:African swine fever is a devastating disease of swine caused by African swine fever virus (ASFV). The pathogenesis of the disease remains largely unknown, leaving the spread of the disease uncontrolled in many countries and regions. Here, we identified E120R, a structural protein of ASFV, as a key virulence factor and late-phase-expressed protein of the virus. E120R revealed an activity to suppress the host antiviral response through blocking beta interferon (IFN-β) production, and the amino acids (aa) at sites 72 and 73 (amino acids 72-73) in the C-terminal domain were essential for this function. E120R interacted with interferon regulatory factor 3 (IRF3) and interfered with the recruitment of IRF3 to TANK-binding kinase 1 (TBK1), which in turn suppressed IRF3 phosphorylation, decreasing interferon production. A recombinant mutant ASFV was further constructed to confirm the claimed mechanism. The ASFV lacking the complete E120R region could not be rescued, whereas the virus could tolerate the deletion of the 72nd and 73rd residues in E120R (ASFV E120R-Δ72-73aa). ASFV E120R with the two-amino-acid deletion failed to interact with IRF3 during ASFV E120R-Δ72-73aa infection, and the viral infection activated IRF3 phosphorylation highly and induced more robust type I interferon production than its parental ASFV. An unbiased transcriptome-wide analysis of gene expression also confirmed that considerably more IFN-stimulated genes (ISGs) were detected in ASFV E120R-Δ72-73aa-infected porcine alveolar macrophages (PAMs) than in wild-type ASFV-infected PAMs. Together, our findings have identified a novel mechanism evolved by ASFV to inhibit the host antiviral response, and they provide a new target for guiding the development of ASFV live-attenuated vaccine. IMPORTANCE African swine fever is a highly contagious animal disease affecting the pig industry worldwide, which has brought enormous economic losses. Infection by the causative agent, African swine fever virus (ASFV), causes severe immunosuppression during viral infection, contributing to serious clinical manifestations. Therefore, identification of the viral proteins involved in immunosuppression is critical for ASFV vaccine design and development. Here, for the first time, we demonstrated that E120R protein, a structural protein of ASFV, played an important role in suppression of interferon regulatory factor 3 (IRF3) phosphorylation and type I interferon production by binding to IRF3 and blocking the recruitment of IRF3 to TANK-binding kinase 1 (TBK1). Deletion of the crucial binding sites in E120R critically increased the interferon response during ASFV infection. This study explored a novel antagonistic mechanism of ASFV, which is critical for guiding the development of ASFV live-attenuated vaccines.

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African Swine Fever Virus CD2v Protein Induces β-Interferon Expression and Apoptosis in Swine Peripheral Blood Mononuclear Cells.

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