Bencherit Djihad, Remy Sylvie, Le Vern Yves, Vychodil Tereza, Bertzbach Luca D, Kaufer Benedikt B, Denesvre Caroline, Trapp-Fragnet Laëtitia
INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
INRA, UMR1282 Infectiologie et Santé Publique, Laboratoire de Cytométrie, Nouzilly, France.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01658-17. Print 2017 Dec 15.
Marek's disease virus (MDV) is a highly contagious alphaherpesvirus that infects chickens and causes a deadly neoplastic disease. We previously demonstrated that MDV infection arrests cells in S phase and that the tegument protein VP22 plays a major role in this process. In addition, expression of VP22 induces double-strand breaks (DSBs) in the cellular DNA, suggesting that DNA damage and the associated cellular response might be favorable for the MDV life cycle. Here, we addressed the role of DNA damage in MDV replication and pathogenesis. We demonstrated that MDV induces DSBs during lytic infection and in the peripheral blood mononuclear cells of infected animals. Intriguingly, we did not observe DNA damage in latently infected MDV-induced lymphoblastoid cells, while MDV reactivation resulted in the onset of DNA lesions, suggesting that DNA damage and/or the resulting DNA damage response might be required for efficient MDV replication and reactivation. In addition, reactivation was significantly enhanced by the induction of DNA damage using a number of chemicals. Finally, we used recombinant viruses to show that VP22 is required for the induction of DNA damage and that this likely contributes to viral oncogenesis. Marek's disease virus is an oncogenic alphaherpesvirus that causes fatal T-cell lymphomas in chickens. MDV causes substantial losses in the poultry industry and is also used in small-animal models for virus-induced tumor formation. DNA damage not only is implicated in tumor development but also aids in the life cycle of several viruses; however, its role in MDV replication, latency, and reactivation remains elusive. Here, we demonstrate that MDV induces DNA lesions during lytic replication and DNA damage was not observed in latently infected cells; however, it was reinitiated during reactivation. Reactivation was significantly enhanced by the induction of DNA damage. Recombinant viruses that lacked the ability to induce DNA damage were defective in their ability to induce tumors, suggesting that DNA damage might also contribute to cellular transformation processes leading to MDV lymphomagenesis.
马立克氏病病毒（MDV）是一种高度传染性的α疱疹病毒，可感染鸡并引发致命的肿瘤性疾病。我们之前证明，MDV感染会使细胞停滞在S期，且被膜蛋白VP22在此过程中起主要作用。此外，VP22的表达会诱导细胞DNA产生双链断裂（DSB），这表明DNA损伤及相关的细胞反应可能对MDV的生命周期有利。在此，我们探讨了DNA损伤在MDV复制和发病机制中的作用。我们证明，MDV在裂解感染期间以及在受感染动物的外周血单核细胞中会诱导DSB。有趣的是，我们在潜伏感染的MDV诱导的淋巴母细胞中未观察到DNA损伤，而MDV再激活会导致DNA损伤的出现，这表明DNA损伤和/或由此产生的DNA损伤反应可能是MDV高效复制和再激活所必需的。此外，使用多种化学物质诱导DNA损伤可显著增强再激活。最后，我们使用重组病毒表明，诱导DNA损伤需要VP22，且这可能有助于病毒致癌作用。马立克氏病病毒是一种致癌性α疱疹病毒，可在鸡中引起致命的T细胞淋巴瘤。MDV给家禽业造成了巨大损失，也被用于病毒诱导肿瘤形成的小动物模型。DNA损伤不仅与肿瘤发展有关，还在几种病毒的生命周期中发挥作用；然而，其在MDV复制、潜伏和再激活中的作用仍不清楚。在此，我们证明MDV在裂解复制期间会诱导DNA损伤，潜伏感染的细胞中未观察到DNA损伤；然而，在再激活期间会重新出现。诱导DNA损伤可显著增强再激活。缺乏诱导DNA损伤能力的重组病毒诱导肿瘤的能力存在缺陷，这表明DNA损伤也可能有助于导致MDV淋巴瘤发生的细胞转化过程。
