UK-China partnership on Global Food Security: Combating avian tumor diseases for sustainable poultry production

传染病在家禽养殖的各个环节造成直接和间接的损失，其中病毒引起的肿瘤病是全球家禽业面临的主要经济问题。在鸡中引起肿瘤感染的致癌病毒是包括马立克氏病病毒（MDV）的疱疹病毒和包括网状内皮组织增生病病毒（REV）和禽白血病病毒（ALV）的逆转录病毒。ALV是最常见的自然发生的禽逆转录病毒，可引起鸡的各种肿瘤性疾病。除了引起肿瘤，ALV已知与受影响的鸡群的生产力降低和其他生产问题有关。根据病毒包膜糖蛋白的性质，ALV分为六个亚组：A、B、C、D、E和J。最初由Pirbright研究所在20世纪80年代后期分离，ALV-J广泛传播并诱导骨髓性白血病和广泛的其他疾病，如组织细胞肉瘤、血管瘤和成红细胞增多症。在欧洲和美国的大多数商业家禽群中，原始毒株几乎已被根除，但在亚洲，该病毒演变成一个很大的品种，最近出现的中国分离株在商业蛋鸡群和中国本地鸡种中诱导各种肿瘤。确定肿瘤发生的分子背景是在中国发展更有效的控制和根除计划所必需的。本研究的目的是通过对ALV-J致癌分子机制的深入研究，了解和预测ALV-J致癌的分子机制。这包括非编码RNA谱分析非编码RNA在ALV-J诱导的肿瘤发生中的作用，癌基因myc靶组鉴定和myc结合在维持转化表型中的作用，以及通过CRISPR/Cas9系统敲除myc在维持转化表型中的作用。由于ALV-J与其他肿瘤病毒如马立克氏病病毒、网状内皮组织增生症病毒等共感染十分常见，且致病作用更为严重，因此我们拟从体内外两方面探讨ALV-J+REV/ALV-J+MDV共感染的协同机制。本研究结果对我国ALV-J的根除和致癌病毒引起的癌症的控制具有重要的参考价值。我们还希望通过CRISPR/Cas9系统编辑ALV-J受体NHE 1，建立耐药细胞系，探索ALV-J的遗传抗性。最后，我们将开发ALV-J感染的快速诊断试剂盒，为我国ALV-J的控制和根除提供帮助。

Infectious diseases result in direct and indirect losses at various steps of poultry farming and amongst them neoplastic disease caused by viruses is a major economic problem faced by the poultry industry worldwide. The oncogenic viruses causing neoplastic infection in chickens are herpesviruses comprising of Marek's disease virus (MDV) and retroviruses comprising of reticuloendotheliosis virus (REV) and avian leucosis virus (ALV). ALV is the most common naturally occurring avian retrovirus that can cause a variety of neoplastic disease conditions in chickens. In addition to causing neoplasia, ALV is known to be associated with reduced productivity and other production problems in affected flocks. Based on the properties of viral envelope glycoproteins, ALV is classified into six subgroups: A, B, C, D, E and J. Originally isolated by the Pirbright Institute in the late 1980s, ALV-J spreads widely and induces myeloid leukosis and a broad spectrum of additional disorders, such as histiocytic sarcoma, hemangiomas and erythroblastosis. The original strains have almost been eradicated from most of the commercial poultry flocks in Europe and the United States but in Asia, the virus evolved into a great variety and recently emerging Chinese isolates coarsely induce various tumours in both commercial laying hen flocks as well as native Chinese breeds of chickens. Defining the molecular background of the tumorigenesisis is needed to develop more effective control and eradication programmes in China. In this proposal, we aim to obtain detailed comprehensive picture on the molecular events to understand and predict the molecular pathways to ALV-J induced cancer. This includes non-coding RNA profiling for the role of non-coding RNAs in ALV-J induced oncogenesis, oncogene myc targetome identification and the role of myc-binding in maintaining the transformed phenotype and myc knockout by CRISPR/Cas9 system for the role of myc in maintaining the transformed phenotype. As the co-infection of ALV-J with other tumor viruses such as Marek's disease virus and Reticuloendotheliosis virus is very common and caused more serious pathogenic effects, we are going to elucidate the synergistic mechanism of ALV-J+REV/ALV-J+MDV co-infection in vitro and in vivo. The findings will be very valuable in developing new approaches for the eradication of ALV-J in China and control of cancers caused by oncogenic viruses. We also want to establish the resistant cell line by editing ALV-J receptor NHE1 using CRISPR/Cas9 system to explore genetic resistant to ALV-J. Finally, we will develop the rapid diagnostic kits to detect ALV-J infection in the field to aid the ALV-J control and eradication in China.