Study on genetic, epigenetic, transcriptomic and proteomic mechanisms modulating sheep resistance to small ruminant lentivirus

小反刍动物慢病毒（SRLV）感染世界各地的动物，造成不可避免的死亡，生产力降低，并因此造成重大的经济损失和动物福利降低。没有治愈或疫苗。已经表明，与宿主对感染和疾病的抗性相关的遗传标记可以应用于动物育种计划。然而，宿主-病原体相互作用是一个复杂的过程，不仅在动物中，而且在人类中大多数研究不足。这种知识的严重缺乏使得通过使用常规以及育种策略来减少病毒威胁变得困难，该项目的目的是：1/鉴定调节绵羊对SRLV抗性的宿主遗传和表观遗传因素，以找到与SRLV抗性相关的可靠遗传标记和表观遗传标记。2/分析SRLV诱导的宿主甲基化组、转录组和蛋白质组的改变，以认识和阐明病毒劫持宿主表观遗传机制和细胞蛋白质组的潜在机制，以及这些过程对宿主-病原体相互作用和宿主对SRLV感染的抗性的影响。3/分析宿主-病毒相互作用中基因组、表观基因组、转录组和蛋白质组因素之间的相互作用机制。计划开展以下研究任务：从SRLV感染的绵羊群中收集动物样品和数据;详细表征SRLV感染状态，例如使用几种血清学测试、qPCR和桑格测序;来自具有不同SRLV感染状态的绵羊的样品的多组学表征（全基因组测序以及全基因组表观遗传、转录组和蛋白质组学分析）;多组学数据分析和对表型和生物信息学结果的整体研究。该项目的结果将提供有关影响慢病毒感染的宿主-病毒相互作用的多组学因素的新知识。此外，拟议的项目有可能提供有关绵羊对SRLV遗传抗性的新基因的证据。另一方面，病毒的表观遗传、转录组和蛋白质组学效应的结果可能表明治愈和预防的新可能性。这样的结果可以为慢病毒感染的额外研究提供新的靶点，所述慢病毒感染可以从SRLV推广到慢病毒家族的其他成员，例如，HIV-1病毒在人类我们期望，采用改进的表观遗传和基因组措施来预防病毒感染，随后将为在不久的将来在动物育种计划中更集中和有效地应用标记辅助或基因组选择以提高对病毒感染的抗性铺平道路。

Small ruminant lentiviruses (SRLV) infect animals worldwide causing inevitable death, lower productivity, and consequently significant economic losses and lower animal welfare. There is no cure or vaccination. It has been shown that genetic markers associated with host resistance to infections and diseases can be applied in animal breeding programs. However, host-pathogen interactions are complex processes, that are mostly understudied not only in animals but also in humans. This substantial lack of knowledge makes viral threat reduction by use of conventional as well as by breeding strategies difficult.The aims of the project are: 1/ To identify host genetic and epigenetic factors which modulate sheep resistance to SRLV in order to find reliable genetic markers and epigenetic marks associated with SRLV resistance. 2/ To analyze SRLV-induced alterations in host methylome, transcriptome, and proteome to recognize and clarify the potential mechanism of hijacking the host epigenetic machinery and the cell proteome by the virus and the impact of these processes on host-pathogen interactions and host resistance to SRLV infection. 3/ To analyze mechanisms of interplay between genomic, epigenomic, transcriptomic, and proteomic factors involved in host-virus interactions.The following research tasks have been planned: Collection of animal samples and data from SRLV infected sheep flocks; detailed characterization of SRLV infection status e.g. by use of several serological tests, qPCR and Sanger sequencing; multi-omics characterization of samples from sheep with diverging SRLV infection status (whole genome sequencing as well as whole genome epigenetic, transcriptomic and proteomic analyses); multi-omics data analysis and holistic study on the phenotypic and bioinformatic results. The results of this project will provide new knowledge on multi-omics factors involved in host-virus interactions influencing a lentiviral infection. Moreover, the proposed project has the potential to deliver evidence on new genes involved in genetic resistance to SRLV in sheep. On the other hand, results on epigenetic, transcriptomic, and proteomic effects of the virus may indicate new possibilities for cure and prophylaxis. Such results can provide new targets for additional investigation into lentiviral infections that may generalize beyond SRLV to other members of the lentiviral family, e.g., HIV-1 virus in humans. We expect that adopting improved epigenetic and genomic measures for the prevention against virus infections will subsequently pave the way for a more focused and efficient application of marker-assisted or genomic selection in animal breeding programs aiming at increasing the resistance to virus infections in the near future.