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

文献类型： 外文期刊

第一作者： Huang, Li

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

作者机构：

关键词： ASFV; H240R gene; NF-kappa B signaling; NLRP3 inflammasome; pathogenicity

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2023 年 97 卷 2 期

页码：

收录情况： SCI

摘要： African swine fever (ASF) is a highly contagious infectious disease of domestic pigs and wild boars caused by African swine fever virus (ASFV), with a mortality rate of up to 100%. In order to replicate efficiently in macrophages and monocytes, ASFV has evolved multiple strategies to evade host antiviral responses. However, the underlying molecular mechanisms by which ASFV-encoded proteins execute immune evasion are not fully understood. In this study, we found that ASFV pH240R strongly inhibits transcription, maturation, and secretion of interleukin-beta (IL-1 beta). Importantly, pH240R not only targeted NF-kB signaling but also impaired NLRP3 inflammasome activation. In this mechanism, pH240R interacted with NF-kappa-B essential modulator (NEMO), a component of inhibitor of kappa B kinase (IKK) complex and subsequently reduced phosphorylation of IkBa and p65. In addition, pH240R bonded to NLRP3 to inhibit NLRP3 inflamma-some activation, resulting in reduced IL-1 beta production. As expected, infection with H240R-deficient ASFV (ASFV-DH240R) induced more inflammatory cytokine expression both in vitro and in vivo than its parental ASFV HLJ/18 strain. Consistently, H240R deficiency reduced the viral pathogenicity in pigs compared with its parental strain. These findings reveal that the H240R gene is an essential virulence factor, and deletion of the H240R gene affects the pathogenicity of ASFV HLJ/18 by enhancing antiviral inflammatory responses, which provides insights for ASFV immune evasion mechanisms and development of attenuated live vaccines and drugs for prevention and control of ASF.

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