African swine fever virus I73R is a critical virulence-related gene: A potential target for attenuation

Abstract

African swine fever virus (ASFV) is a large, double-stranded DNA virus that causes a fatal disease in pigs, posing a threat to the global pig industry. Whereas some ASFV proteins have been found to play important roles in ASFV–host interaction, the functional roles of many proteins are still largely unknown. In this study, we identified I73R , an early viral gene in the replication cycle of ASFV, as a key virulence factor. Our findings demonstrate that pI73R suppresses the host innate immune response by broadly inhibiting the synthesis of host proteins, including antiviral proteins. Crystallization and structural characterization results suggest that pI73R is a nucleic-acid-binding protein containing a Zα domain. It localizes in the nucleus and inhibits host protein synthesis by suppressing the nuclear export of cellular messenger RNA (mRNAs). While pI73R promotes viral replication, the deletion of the gene showed that it is a nonessential gene for virus replication. In vivo safety and immunogenicity evaluation results demonstrate that the deletion mutant ASFV-GZΔ I73R is completely nonpathogenic and provides effective protection to pigs against wild-type ASFV. These results reveal I73R as a virulence-related gene critical for ASFV pathogenesis and suggest that it is a potential target for virus attenuation. Accordingly, the deletion mutant ASFV-GZΔ I73R can be a potent live-attenuated vaccine candidate.

African swine fever virus early protein pI73R suppresses the type-I IFN promoter activities

“…ASFV I73R is a high-affinity Z-DNA binding protein ( Liu et al, 2023 ; Sun et al, 2022a ). Three residues, Asn44, Tyr48, and Trp68, are critical for its Z-DNA binding activity ( Sun et al, 2022a ).…”

“…As the infection progresses, the protein relocates to the cell cytoplasm. Previous studies demonstrated that I73R is not essential for viral replication in cell cultures ( Liu et al, 2023 ). However, deletion of the I73R gene from the genome of a virulent ASFV strain completely abolished the virus virulence when tested in pigs.…”

African Swine Fever Virus Protein B263R Inhibits Autophagy by Promoting Proteasomal Degradation of Beclin1

“…There are currently no commercial vaccines against ASFV, which limiting the control of ASF worldwide. Recombinant ASFV with deletions of various virulence-related genes that induce a powerful effect, have received much attention in recent decades (25). Understanding the interplay between ASFV gene functions and host responses is crucial for elucidating virus characteristics and identifying potential targets for virus attenuation.…”

Identification of an Immunodominant B-Cell Epitope in African Swine Fever Virus p30 Protein and Evidence of p30 Antibody-Mediated Antibody Dependent Cellular Cytotoxicity

“…This protein binds to cellular mRNAs and prevents their translation, therefore suppressing host innate immune responses and promoting viral replication. Animals inoculated with a I73R deleted mutant virus showed no clinical manifestations and cleared the infection after 28 days [29].…”