A Common Live-Attenuated Avian Herpesvirus Vaccine Expresses a Very Potent Oncogene
A Common Live-Attenuated Avian Herpesvirus Vaccine Expresses a Very Potent Oncogene
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DOI：
10.1128/msphere.00658-19
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Kaufer, Benedikt B.
中科院分区：
文献类型：
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作者：
Conradie, Andele M.;Bertzbach, Luca D.;Kaufer, Benedikt B.
疫苗在保护动物和人类免受致命病原体侵害方面发挥着至关重要的作用。第一种也能预防癌症的疫苗是针对高致癌性疱疹病毒马立克氏病病毒 (MDV) 开发的。 MDV 感染鸡并导致严重的免疫抑制、神经系统症状和致命的淋巴瘤，这一过程需要病毒癌基因 meq。最常用的马立克氏病疫苗是减毒活疫苗 CVI988/Rispens (CVI) 株，可有效保护鸡并预防肿瘤发生。有趣的是，CVI 表达至少两种 meq 亚型；然而，目前尚不清楚这些异构体在多大程度上有助于病毒减毒。在这项研究中，我们单独检查了两种 CVI-meq 异构体对疫苗减毒的贡献。我们将各自的同种型插入毒性很强的 MDV（RB-1B 株）中，从而取代了其原始的 meq 基因。令人惊讶的是，我们可以证明较长的 meq 亚型强烈增强了病毒诱导的发病机制和肿瘤发生，表明 CVI 基因组中的其他突变有助于病毒减毒。相反，较短的亚型完全消除了发病机制，这表明 meq 基因的变化确实可以在病毒减毒中发挥关键作用。总而言之，我们的研究为全球最常用的兽用疫苗之一的减毒提供了重要证据。 重要性 马立克氏病病毒 (MDV) 是几种致癌性疱疹病毒之一，可导致鸡致命性淋巴瘤。目前的“金标准”疫苗是减毒活MDV毒株CVI988/Rispens (CVI)，该疫苗被广泛使用并有效预防肿瘤形成。有趣的是，CVI 表达主要 MDV 癌基因 meq 的两种主要亚型：一种具有常规大小 meq (Smeq) 的变体和一种在反式激活结构域中插入 180 bp 的长亚型 (Lmeq)。在我们的研究中，我们可以打破长期以来的假设，即 Lmeq 同工型是病毒减毒的指标。使用表达不同 CVI-meq 同工型的重组病毒，我们可以证明两种同工型在促进受感染鸡的发病机制和肿瘤形成的能力方面存在显着差异。
Vaccines play a crucial role in the protection of animals and humans from deadly pathogens. The first vaccine that also protected against cancer was developed against the highly oncogenic herpesvirus Marek's disease virus (MDV). MDV infects chickens and causes severe immunosuppression, neurological signs, and fatal lymphomas, a process that requires the viral oncogene, meq. The most frequently used Marek's disease vaccine is the live-attenuated CVI988/Rispens (CVI) strain, which efficiently protects chickens and prevents tumorigenesis. Intriguingly, CVI expresses at least two isoforms of meq; however, it remains unknown to what extent these isoforms contribute to virus attenuation. In this study, we individually examined the contribution of the two CVI-meq isoforms to the attenuation of the vaccine. We inserted the respective isoforms into a very virulent MDV (strain RB-1B), thereby replacing its original meq gene. Surprisingly, we could demonstrate that the longer isoform of meq strongly enhanced virus-induced pathogenesis and tumorigenesis, indicating that other mutations in the CVI genome contribute to virus attenuation. On the contrary, the shorter isoform completely abrogated pathogenesis, demonstrating that changes in the meq gene can indeed play a key role in virus attenuation. Taken together, our study provides important evidence on attenuation of one of the most frequently used veterinary vaccines worldwide.IMPORTANCE Marek's disease virus (MDV) is one of several oncogenic herpesviruses and causes fatal lymphomas in chickens. The current "gold standard" vaccine is the live-attenuated MDV strain CVI988/Rispens (CVI), which is widely used and efficiently prevents tumor formation. Intriguingly, CVI expresses two predominant isoforms of the major MDV oncogene meq: one variant with a regular size of meq (Smeq) and one long isoform (Lmeq) harboring an insertion of 180 bp in the transactivation domain. In our study, we could break the long-standing assumption that the Lmeq isoform is an indicator for virus attenuation. Using recombinant viruses that express the different CVI-meq isoforms, we could demonstrate that both isoforms drastically differ in their abilities to promote pathogenesis and tumor formation in infected chickens.