Deletion of African swine fever virus interferon inhibitors from the genome of a virulent isolate reduces virulence in domestic pigs and induces a protective response.
Deletion of African swine fever virus interferon inhibitors from the genome of a virulent isolate reduces virulence in domestic pigs and induces a protective response.
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DOI：
10.1016/j.vaccine.2016.08.011
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发表时间：
2016-09-07
期刊：
影响因子：
5.5
通讯作者：
Dixon LK
中科院分区：
文献类型：
--
作者：
Reis AL;Abrams CC;Goatley LC;Netherton C;Chapman DG;Sanchez-Cordon P;Dixon LK
非洲猪瘟病毒（ASFV）编码多拷贝的MGF 360和MGF 530/505基因家族。这些基因与I型干扰素（IFN）应答的调节有关。我们研究了通过删除基因MGF 360来调节IFN应答对病毒减毒和诱导保护性免疫的影响。（MGF360- 10 L、11 L、12 L、13 L、14 L）和MGF530/505在本发明的实施方案中，本发明涉及强毒ASFV分离株Benin 97/1的基因组中的突变基因（MGF 530/505- 1 R、2 R和3R）和中断基因（MGF 360 - 9 L和MGF 530/505- 4 R）。这种缺失突变体BeninΔMGF在猪巨噬细胞中的体外复制与亲本强毒病毒Benin 97/1和天然减毒分离物OURT 88/3相似，后者具有类似的MGF 360和530/505基因缺失。IFN-β mRNA水平在强毒Benin 97/1分离株感染的巨噬细胞中几乎检测不到，但在OURT 88/3感染的巨噬细胞中检测到高水平，而在BeninΔMGF感染的巨噬细胞中检测到中等水平。这些数据证实了这些MGF 360和MGF 530/505基因在抑制I型IFN的诱导中具有作用。用BeninΔMGF免疫和加强猪表明病毒被减毒，并且所有猪（5/5）都保护免于用致死剂量的强毒Benin 97/1攻击。在免疫后第5或6天观察到短暂的一过性发热，但无其他临床体征。在用OURT 88/3分离株免疫和加强后，4头猪中有3头受到保护免于攻击。与OURT 88/3相比，在用贝宁ΔMGF免疫的猪中观察到细胞和抗体应答的差异。干扰素调节因子的缺失是构建合理减毒ASFV候选疫苗株的一条有前途的途径。
African swine fever virus (ASFV) encodes multiple copies of MGF360 and MGF530/505 gene families. These genes have been implicated in the modulation of the type I interferon (IFN) response. We investigated the effect of modulating the IFN response on virus attenuation and induction of protective immunity by deleting genes MGF360 (MGF360-10L, 11L, 12L, 13L, 14L) and MGF530/505 (MGF530/505-1R, 2R and 3R) and interrupting genes (MGF360-9L and MGF530/505-4R) in the genome of the virulent ASFV isolate Benin 97/1. Replication of this deletion mutant, BeninΔMGF, in porcine macrophages in vitro was similar to that of the parental virulent virus Benin 97/1 and the natural attenuated isolate OURT88/3, which has a similar deletion of MGF360 and 530/505 genes. Levels of IFN-β mRNA in macrophages infected with virulent Benin 97/1 isolate were barely detectable but high levels were detected in macrophages infected with OURT88/3 and intermediate levels in macrophages infected with BeninΔMGF. The data confirms that these MGF360 and MGF530/505 genes have roles in suppressing induction of type I IFN. Immunisation and boost of pigs with BeninΔMGF showed that the virus was attenuated and all pigs (5/5) were protected against challenge with a lethal dose of virulent Benin 97/1. A short transient fever was observed at day 5 or 6 post-immunisation but no other clinical signs. Following immunisation and boost with the OURT88/3 isolate 3 of 4 pigs were protected against challenge. Differences were observed in the cellular and antibody responses in pigs immunised with BeninΔMGF compared to OURT88/3. Deletion of IFN modulators is a promising route for construction of rationally attenuated ASFV candidate vaccine strains.
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