African Swine Fever Virus HLJ/18 CD2v Suppresses Type I IFN Production and IFN-Stimulated Genes Expression through Negatively Regulating cGMP-AMP Synthase-STING and IFN Signaling Pathways.
African Swine Fever Virus HLJ/18 CD2v Suppresses Type I IFN Production and IFN-Stimulated Genes Expression through Negatively Regulating cGMP-AMP Synthase-STING and IFN Signaling Pathways.
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DOI：
10.4049/jimmunol.2200813
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发表时间：
2023-05-01
期刊：
影响因子：
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通讯作者：
Weng, Changjiang
中科院分区：
文献类型：
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作者：
Huang, Li;Chen, Weiye;Weng, Changjiang
非洲猪瘟是由非洲猪瘟病毒（ASFV）引起的一种致死性传染病。这种传染病造成的高死亡率是对全球养猪业的重大挑战。ASFV的毒力与其拮抗IFN应答的能力有关，但其拮抗机制尚不清楚。最近，已经出现了在亲本ASFV HLJ/18（ASFV-DeltaEP 402 R）毒株内具有EP 402 R基因缺失的毒性较低的重组病毒。EP 402 R基因编码CD 2 v。因此，我们推测ASFV使用CD 2 v蛋白来逃避I型IFN介导的先天免疫应答。我们发现，与亲本ASFV HLJ/18相比，ASFV-DeltaEP 402 R感染诱导更高的I型IFN应答，并增加猪肺泡巨噬细胞中IFN刺激基因的表达。与这些结果一致，CD 2 v过表达抑制I型IFN的产生和IFN刺激的基因表达。从机制上讲，CD 2 v通过与IFN基因刺激因子（STING）的跨膜结构域相互作用，阻止STING转运到高尔基体，从而抑制cGMP-AMP激酶-STING信号通路。此外，ASFV CD 2 v破坏IFNAR 1-TYK 2和IFNAR 2-JAK 1相互作用，从而抑制IFN-α对JAK-STAT的激活。在体内，用突变ASFV-DeltaEP 402 R毒株感染的无特定病原体的猪比用亲本ASFV HLJ/18毒株感染的动物存活得更好。与该发现一致，ASFV-DeltaEP 402 R攻击的猪的外周血中的IFN-β蛋白水平显著高于ASFV HLJ/18攻击的猪的血液中的IFN-β蛋白水平。综上所述，我们的研究结果表明，CD 2 v抑制cGMP-AMP酶-STING和IFN信号通路以逃避先天免疫应答从而使ASFV感染在猪中致命的分子机制。
African swine fever is a fatal infectious disease caused by African swine fever virus (ASFV). The high mortality caused by this infectious disease is a significant challenge to the swine industry worldwide. ASFV virulence is related to its ability to antagonize IFN response, yet the mechanism of antagonism is not understood. Recently, a less virulent recombinant virus has emerged that has a EP402R gene deletion within the parental ASFV HLJ/18 (ASFV-DeltaEP402R) strain. EP402R gene encodes CD2v. Hence we hypothesized that ASFV uses CD2v protein to evade type I IFN-mediated innate immune response. We found that ASFV-DeltaEP402R infection induced higher type I IFN response and increased the expression of IFN-stimulated genes in porcine alveolar macrophages when compared with parental ASFV HLJ/18. Consistent with these results, CD2v overexpression inhibited type I IFN production and IFN-stimulated gene expression. Mechanistically, CD2v, by interacting with the transmembrane domain of stimulator of IFN genes (STING), prevented the transport of STING to the Golgi apparatus, and thereby inhibited the cGMP-AMP synthase-STING signaling pathway. Furthermore, ASFV CD2v disrupted IFNAR1-TYK2 and IFNAR2-JAK1 interactions, and thereby inhibited JAK-STAT activation by IFN-alpha. In vivo, specific pathogen-free pigs infected with the mutant ASFV-DeltaEP402R strain survived better than animals infected with the parental ASFV HLJ/18 strain. Consistent with this finding, IFN-beta protein levels in the peripheral blood of ASFV-DeltaEP402R-challenged pigs were significantly higher than in the blood of ASFV HLJ/18-challenged pigs. Taken together, our findings suggest a molecular mechanism in which CD2v inhibits cGMP-AMP synthase-STING and IFN signaling pathways to evade the innate immune response rendering ASFV infection fatal in pigs.