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

Abstract

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.

Exploring type I interferon pathway: virulent vs. attenuated strain of African swine fever virus revealing a novel function carried by MGF505-4R

“…While an increasing number of reports have illustrated how ASFV has evolved various mechanisms to counteract IFN-α/β signaling ( 16 , 17 , 25 , 27 , 72 – 74 ), this marks the first description of ASFV targeting TRAF3. Altogether, this emphasizes the evolution of ASFV to encode numerous viral proteins with redundant functions in immune evasion.…”

“…This variation is mainly due to the loss or gain of genes within the Multigene families (MGF) ( 14 ). Previous works suggest that genes within MGF360 and MGF505 are crucial in the modulation of the type I Interferon (IFN-α/β) signaling pathway ( 15 – 17 ). Moreover, attenuated ASFV strains, exhibiting the loss or truncation of various MGF360 and 505 genes, are more sensitive to IFN-α in comparison to their virulent counterparts ( 18 – 21 ).…”

Infection of domestic pigs with a genotype II potent strain of ASFV causes cytokine storm and lymphocyte mass reduction

“…ASFV predominantly infects the monocyte-macrophage system, including circulating monocytes, intra-tissue macrophages, and dendritic cells, providing a favorable environment for ASFV replication and infection. These cells play an important role in host innate and adaptive immunity; therefore, ASFV can inhibit host immunity and evade innate and adaptive immune responses ( 5 ). It can evade host immunity through multiple pathways, which mainly include the inhibition of IFN secretion through signaling pathways such as cGAS-STING and JAK-STAT ( 6 – 10 ); moreover, it inhibits IFN secretion through signaling pathways such as NF-κB to impede the host inflammatory response ( 11 , 12 ) and the apoptosis of infected cells ( 13 – 15 ).…”

Functional Landscape of African Swine Fever Virus–Host and Virus–Virus Protein Interactions

“…ASFV evolved many strategies for cellular entry and trafficking, formation of virus replication complexes, assembly of virions, and counter-defense of host immune responses, which have been extensively reviewed previously [ 7 , 8 , 9 , 10 , 11 ]. Given such a large number of proteins and the complex morphogenesis and replication strategy, a high number of specific virus–host protein–protein interactions (PPIs) can be expected to be implemented during infection to reprogram the host environment for efficient virus replication and immune evasion.…”