Deletion of MGF‐110‐9L gene from African swine fever virus weakens autophagic degradation of TBK1 as a mechanism for enhancing type I interferon production

Abstract

African swine fever (ASF) caused by African swine fever virus (ASFV) is a devastating disease for the global pig industry and economic benefit. The limited knowledge on the pathogenesis and infection mechanisms of ASF restricts progress toward vaccine development and ASF control. Previously, we illustrated that deletion of the MGF-110-9L gene from highly virulent ASFV CN/GS/2018 strains (ASFV∆9L) results in attenuated virulence in swine, but the underlying mechanism remains unclear. In this study, we found that the difference in virulence between wild-type ASFV (wt-ASFV) and ASFV∆9L strains was mainly caused by the difference in TANK Binding Kinase 1 (TBK1) reduction. TBK1 reduction was further identified to be mediated by the autophagy pathway and this degradative process requires the up-regulation of a positive autophagy regulation molecule-Phosphatidylinositol-4-Phosphate 3-Kinase Catalytic Subunit Type 2 Beta (PIK3C2B). Moreover, TBK1 over-expression was confirmed to inhibit ASFV replication in vitro. In summary, these results indicate that wt-ASFV counteracts type I interferon (IFN) production by degrading TBK1, while ASFVΔ9L enhanced type I IFN production by weakening TBK1 reduction, clarifying the mechanism that ASFVΔ9L present the attenuated virulence in vitro.

SNX32 is a host restriction factor that degrades African swine fever virus CP204L via the RAB1B-dependent autophagy pathway

“…In general, this study identified a potential target for the development of novel antiviral therapeutic strategies. On the other hand, based on current research findings, many viral proteins participated in the regulation of autophagy, such as A137R, MGF-505-7R, K205R, L83L, E199L, A179L, and MGF-110-9L ( 38 , 40 – 43 , 53 , 54 ). Thus, we concluded that autophagy may play an important role in the regulation of ASFV replication, and the mechanism between viral protein and autophagy deserves further study.…”

Deletion of MGF505-2R Gene Activates the cGAS-STING Pathway Leading to Attenuation and Protection against Virulent African Swine Fever Virus

“…Some of these viral proteins seem to affect the first steps of the pathway, such as the QP383R that interacts with cGAS, preventing DNA binding [13] or C129R and EP364R that degrade cGAMP [12]. Other ASFV proteins counteract TBK1 action by inducing its degradation, as A137R [18], MGF-110-9L [17], MGF360-11L or MGF505-7R do, the two latter further interacting with IRF7 [48,49]; while others degrade IRF3, such as M1249L or MGF360-14L [50,51] or inhibit its activation, such as E120R, E301R or S137R [52][53][54]. Multiple ASFV proteins seem to interact with STING, leading to counteract its activation, such as B175L, D117L (P17), MGF-505-7R, MGF505-11R, EP402R (CD2v) or L83L [14][15][16]19,55,56].…”

“…We first hypothesized that the absence of this protein was linked to virulence in domestic pigs, similar to other ASFV proteins involved in the control of the cGAS/STING pathway, which have been found to be directly related to virulence. Examples of that would be ASFV MGF-505-7R [15], A137R [18,33], or MGF-110-9L [17,59].…”

“…In this regard, our group described that the cGAS/STING pathway is only efficiently controlled by virulent ASFV strains, while attenuated ASFV strain infection leads to IFN-β production [11]. Subsequent studies have reinforced this finding, identifying a multitude of viral factors that control some of the elements of the cGAS/STING pathway [12][13][14][15][16][17][18][19]. The type I IFN-induced JAK/STAT pathway has also been described as being controlled by ASFV [20], further relating type I IFN to virulence.…”