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

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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.