Combinational Deletions of MGF110-9L and MGF505-7R Genes from the African Swine Fever Virus Inhibit TBK1 Degradation by an Autophagy Activator PIK3C2B To Promote Type I Interferon Production

Abstract

African swine fever (ASF) is a contagious and lethal hemorrhagic disease of pigs caused by the African swine fever virus (ASFV), leading to significant economic consequences for the global pig industry. The development of an effective and safe ASF vaccine has been unsuccessful.

The MGF300-2R protein of African swine fever virus is associated with viral pathogenicity by promoting the autophagic degradation of IKKα and IKKβ through the recruitment of TOLLIP

“…This study provided the first evidence of the role of the MGF300-2R gene, for which the function was unknown. We analyzed whether there are differences in binding, internalization, virus particle release, and viral factory formation between the Del2R and ASFV-WT, but no significant differences were observed (S3 Fig) . Recently, it has been found that the MGFs (MGF110-9L, MGF360-9L, and MGF505-7R) are involved in ASFV virulence and immune evasion [13][14][15][16]. We observed an increase in the expression levels of the NF-κB mediated proinflammatory cytokines IL-1β and TNF-α in the Del2R-infected PAMs, as indicated using RNA-seq, RT-qPCR, and ELISA analysis (Fig 2).…”

“…A viral protein can play a regulatory role at different levels of the NF-κB and IFN signaling pathways. For example, the virulence-associated protein MGF505-7R of ASFV can interact with IKKα and multiple adaptors of the IFN signaling pathway, including STING, IRF9, IRF3, JAK1, and JAK2 to inhibit IL-1β and IFN production, respectively [13][14][15][16]49]. Recently, numerous studies have demonstrated that the IFN inhibitors of ASFV are likely to influence viral replication and pathogenicity [50].…”

“…Remarkably, single-gene deletion of the ASFV NF-κB inhibitors affects viral pathogenesis and virulence variably. The diverse NF-κB inhibitors encoded by ASFV, along with the possibility of overlapping or complementary functions, may explain this observation [13][14][15][16]40].…”

“…Recent studies have shown that the MGF505-7R protein can antagonize the production of interferon (IFN) and inflammatory cytokines in PAMs and pigs [12]. More importantly, the deletion of the MGF505-7R gene from a virulent strain partially attenuated its virulence in pigs [13][14][15][16]. The pandemic of ASF highlights the importance of studying the molecular mechanism of individual MGFs involved in pathogenesis, which is still largely unknown [17,18].…”