Differential Effect of Deleting Members of African Swine Fever Virus Multigene Families 360 and 505 from the Genotype II Georgia 2007/1 Isolate on Virus Replication, Virulence, and Induction of Protection.
Differential Effect of Deleting Members of African Swine Fever Virus Multigene Families 360 and 505 from the Genotype II Georgia 2007/1 Isolate on Virus Replication, Virulence, and Induction of Protection.
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DOI：
10.1128/jvi.01899-21
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发表时间：
2022-03-23
影响因子：
5.4
通讯作者：
Dixon LK
中科院分区：
文献类型：
--
作者：
Rathakrishnan A;Connell S;Petrovan V;Moffat K;Goatley LC;Jabbar T;Sánchez-Cordón PJ;Reis AL;Dixon LK
非洲猪瘟病毒多基因家族（MGF） 360和505基因在猪体内抑制I型干扰素反应和毒力中发挥作用。人们对个体基因的作用知之甚少。这些基因的不同组合从格鲁吉亚2007/1毒力基因型II分离株中删除。删除mgf360基因MGF360-10L、-11L、-12L、-13L和-14L的5个拷贝，以及MGF505-1R、-2R和-3R的3个拷贝，减少了病毒在猪体内巨噬细胞和减毒病毒中的复制。然而，只有25%的免疫猪免受攻击。MGF360-12L、-13L、-14L和MGF505-1R的缺失与阴性血清学标记物K145R （GeorgiaΔK145RΔMGF(a)）联合，减少了病毒在巨噬细胞中的复制和猪的毒力，因为免疫后没有观察到临床症状或血液中的病毒基因组。6头猪中有4头在挑战后得到保护。相反，MGF360-13L和-14L、MGF505-2R和-3R以及K145R （GeorgiaΔK145RΔMGF(B)）的缺失并没有减少病毒在巨噬细胞中的复制。在猪的免疫接种后，临床症状延迟，但所有猪都达到了人道终点。MGF360-12L、MGF505-1R和K145R基因的缺失减少了巨噬细胞的复制，降低了猪的毒力，因为免疫后没有观察到临床症状或血液中的病毒基因组。因此，MGF360-12L和MGF505-1R的缺失与K145R的结合足以显著减弱猪的病毒感染。然而，6只猪中只有2只受到保护，这表明需要删除额外的MGF基因来诱导保护性免疫反应。从GeorgiaΔK145R病毒中删除MGF360-12L，而不是MGF505-1R，减少了病毒在巨噬细胞中的复制，这表明MGF360-12L对于维持巨噬细胞中高水平的病毒复制最为关键。非洲猪瘟具有高度的社会经济影响，并且没有疫苗来帮助控制。非洲猪瘟病毒（ASFV）有许多抑制宿主干扰素反应的基因。这些基因包括与多基因家族相关的基因，包括MGF360和505。在这里，我们研究了MGF360和505基因对病毒衰减和保护在欧洲和亚洲流行的II型病毒最重要的基因。我们比较了MGF基因缺失的病毒。只需删除两个MGF基因与第三个基因K145R（一种可能的疫苗接种标记）结合，就足以使猪体内的病毒衰减。需要删除额外的MGF360基因来诱导更高水平的保护。此外，我们发现MGF360-12L的缺失与K145R的结合会削弱培养巨噬细胞中的病毒复制。我们的研究结果对了解ASFV MGF基因的作用和疫苗开发具有重要意义。
African swine fever virus multigene family (MGF) 360 and 505 genes have roles in suppressing the type I interferon response and in virulence in pigs. The role of the individual genes is poorly understood. Different combinations of these genes were deleted from the virulent genotype II Georgia 2007/1 isolate. Deletion of five copies of MGF 360 genes, MGF360-10L, -11L, -12L, -13L, and -14L, and three copies of MGF505-1R, -2R, and -3R reduced virus replication in macrophages and attenuated virus in pigs. However, only 25% of the immunized pigs were protected against challenge. Deletion of MGF360-12L, -13L, and -14L and MGF505-1R in combination with a negative serology marker, K145R (GeorgiaΔK145RΔMGF(A)), reduced virus replication in macrophages and virulence in pigs, since no clinical signs or virus genome in blood were observed following immunization. Four of six pigs were protected after challenge. In contrast, deletion of MGF360-13L and -14L, MGF505-2R and -3R, and K145R (GeorgiaΔK145RΔMGF(B)) did not reduce virus replication in macrophages. Following immunization of pigs, clinical signs were delayed, but all pigs reached the humane endpoint. Deletion of genes MGF360-12L, MGF505-1R, and K145R reduced replication in macrophages and attenuated virulence in pigs since no clinical signs or virus genome in blood were observed following immunization. Thus, the deletion of MGF360-12L and MGF505-1R, in combination with K145R, was sufficient to dramatically attenuate virus infection in pigs. However, only two of six pigs were protected, suggesting that deletion of additional MGF genes is required to induce a protective immune response. Deletion of MGF360-12L, but not MGF505-1R, from the GeorgiaΔK145R virus reduced virus replication in macrophages, indicating that MGF360-12L was most critical for maintaining high levels of virus replication in macrophages. IMPORTANCE African swine fever has a high socioeconomic impact and no vaccines to aid control. The African swine fever virus (ASFV) has many genes that inhibit the host’s interferon response. These include related genes that are grouped into multigene families, including MGF360 and 505. Here, we investigated which MGF360 and 505 genes were most important for viral attenuation and protection against genotype II strains circulating in Europe and Asia. We compared viruses with deletions of MGF genes. Deletion of just two MGF genes in combination with a third gene, K145R, a possible marker for vaccination, is sufficient for virus attenuation in pigs. Deletion of additional MGF360 genes was required to induce higher levels of protection. Furthermore, we showed that the deletion of MGF360-12L, combined with K145R, impairs virus replication in macrophages in culture. Our results have important implications for understanding the roles of the ASFV MGF genes and for vaccine development.
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