Deletion of African Swine Fever Virus (ASFV) H240R Gene Attenuates the Virulence of ASFV by Enhancing NLRP3-Mediated Inflammatory Responses

Huang, Li; Li, Hongyang; Ye, Guangqiang; Liu, Xiaohong; Chen, Weiye; Wang, Zilong; Zhao, Dongming; Zhang, Zhaoxia; Feng, Chunying; Hu, Liang; Yu, Huibin; Zhou, Shijun; Zhang, Xianfeng; He, Xijun; Zheng, Jun; Bu, Zhigao; Li, Jiangnan; Weng, Changjiang

doi:10.1128/jvi.01227-22

Cited by 19 publications

(20 citation statements)

References 39 publications

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“…Notably, MGF300-4L is among several ASFV proteins including, H240R, MGF505-7R, and MGF300-2R, all of which inhibit NF- κ B activation. When deleted individually from ASFV, they cause an attenuation phenotype in vivo [ 13 , 26 , 27 ]. Intuitively, it seems unlikely that the attenuation would occur due to the loss of a single NF- κ B inhibitor, especially when other inhibitors are still present.…”

Section: Discussionmentioning

confidence: 99%

The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK β and increasing the stability of I κ B α

Wang,

Luo,

Zhang

et al. 2024

Emerging Microbes & Infections

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African swine fever (ASF) is a highly contagious, often fatal viral disease caused by African swine fever virus (ASFV), which imposes a substantial economic burden on the global pig industry. When screening for the virus replication-regulating genes in the left variable region of the ASFV genome, we observed a notable reduction in ASFV replication following the deletion of the MGF300-4L gene. However, the role of MGF300-4L in ASFV infection remains unexplored. In this study, we found that MGF300-4L could effectively inhibit the production of proinflammatory cytokines IL-1 β and TNF- α , which are regulated by the NF- κ B signaling pathway. Mechanistically, we demonstrated that MGF300-4L interacts with IKK β and promotes its lysosomal degradation via the chaperone-mediated autophagy. Meanwhile, the interaction between MGF300-4L and I κ B α competitively inhibits the binding of the E3 ligase β -TrCP to I κ B α , thereby inhibiting the ubiquitination-dependent degradation of I κ B α . Remarkably, although ASFV encodes other inhibitors of NF- κ B, the MGF300-4L gene-deleted ASFV (Del4L) showed reduced virulence in pigs, indicating that MGF300-4L plays a critical role in ASFV pathogenicity. Importantly, the attenuation of Del4L was associated with a significant increase in the production of IL-1 β and TNF- α early in the infection of pigs. Our findings provide insights into the functions of MGF300-4L in ASFV pathogenicity, suggesting that MGF300-4L could be a promising target for developing novel strategies and live attenuated vaccines against ASF.

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Section: Discussionmentioning

confidence: 99%

The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK β and increasing the stability of I κ B α

Wang,

Luo,

Zhang

et al. 2024

Emerging Microbes & Infections

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“…After deleting these genes individually from highly virulent ASFV strains, a significant decrease in pathogenicity and virulence can be observed in the mutants ( Table 2 ). Previous studies have confirmed that deletion of the H240R gene will enhance NLRP3-mediated inflammatory responses, resulting in the attenuation of ASFV [ 112 ]. Of note, MGF505-7R has proven to be a multifunctional protein, playing crucial roles in suppressing cGAS-STING-mediated IFN-I production, IFN-II-induced antiviral response, and NLRP3 inflammasome activation [ 65 ].…”

Section: Effects Of Immune Evasion On Viral Replication and Virulencementioning

confidence: 96%

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

Zhu

Deng³

et al. 2023

Viruses

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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.

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“…ASFV pH240R serves as a robust suppressor of IL-1β transcription, maturation, and secretion, along with restraining NLRP3 inflammasome activation in inflammatory responses ( Huang et al , 2023 ). Its inhibitory actions extend beyond NF-κB signaling to encompass NLRP3 inflammasome activation.…”

Section: Introductionmentioning

confidence: 99%

“…These findings underscore the pivotal role of pH240R in ASFV virulence, indicating its potential as a subject for in-depth exploration into ASFV immune evasion mechanisms. Such investigations may pave the way for the development of attenuated live vaccines and therapeutic interventions for effective ASF prevention and control ( Huang et al , 2023 ).…”

Section: Introductionmentioning

confidence: 99%

African swine fever virus proteins against host antiviral innate immunity and their implications for vaccine development

Orosco

2024

Open Vet J

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African Swine Fever Virus (ASFV) poses a significant threat to global swine populations, necessitating a profound understanding of viral strategies against host antiviral innate immunity. This review synthesizes current knowledge regarding ASFV proteins and their intricate interactions with host defenses. Noteworthy findings encompass the modulation of interferon signaling, manipulation of inflammatory pathways, and the impact on cellular apoptosis. The implications of these findings provide a foundation for advancing vaccine strategies against ASFV. In conclusion, this review consolidates current knowledge, emphasizing the adaptability of ASFV in subverting host immunity. Identified research gaps underscore the need for continued exploration, presenting opportunities for developing targeted vaccines. This synthesis provides a roadmap for future investigations, aiming to enhance our preparedness against the devastating impact of ASFV on global swine populations.

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Deletion of African Swine Fever Virus (ASFV) H240R Gene Attenuates the Virulence of ASFV by Enhancing NLRP3-Mediated Inflammatory Responses

Abstract: African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly contagious and acute hemorrhagic viral disease of domestic pigs, with a high mortality approaching 100%. ASFV has spread rapidly worldwide and caused huge economic losses and ecological consequences.

Cited by 19 publications

References 39 publications

The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK β and increasing the stability of I κ B α

The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK β and increasing the stability of I κ B α

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

African swine fever virus proteins against host antiviral innate immunity and their implications for vaccine development

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