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.

African Swine Fever Virus pE199L Induces Mitochondrial-Dependent Apoptosis

“…Recently, CD2v was reported to induced apoptosis by NF-κB in swine peripheral blood mononuclear cells [46]. However, CD2v was not identified in our screening system because released CD2v may require ligands such as CD58 to activate downstream death programs [46]. ASFV pE199L was identified as having the most significant effect in our screening system.…”

“…ASFV pE183L/p54 has been reported to cause apoptosis via the mitochondrial apoptotic pathway in Vero cells [23]. Recently, CD2v was reported to induced apoptosis by NF-κB in swine peripheral blood mononuclear cells [46]. However, CD2v was not identified in our screening system because released CD2v may require ligands such as CD58 to activate downstream death programs [46].…”

Transcriptome profile of spleen tissues from locally-adapted Kenyan pigs (Sus scrofa) experimentally infected with three varying doses of a highly virulent African swine fever virus genotype IX isolate: Ken12/busia.1 (ken-1033)

“…Interferons (IFNs) form part of the first line of defense against viral infections and play a substantial role in the early immune response cells [ 109 ]. IFNs provide host defense against viral infections by inducing the expression of numerous IFN-stimulated genes (ISGs), activating host antiviral immunity [ 26 , 110 ]. We detected significant upregulation of TNF inflammatory cytokines (Table 3 ).…”

Immune Escape Mechanism and Vaccine Research Progress of African Swine Fever Virus

“…pI215L recruits RNF138 to inhibit K63-related TBK1 ubiquitination, which has an inhibitory effect on IFN-I production [ 49 ]. It is worth noting that CD2V can activate NF-κB and induce activation of IFN signaling pathways in porcine lymphocytes/macrophages [ 50 ]. These immunosuppressive genes are potential target genes for the preparation of live attenuated vaccines.…”