Characterization of the immunogenome in Old World camelids

Dromedary and Bactrian camels are important domestic animals, well adapted to harsh conditions and resistant to devastating infections that threaten other livestock species in the same areas like trypanosomiasis and foot-and-mouth disease. Other infections have an important role in husbandry and in human health, such as the Middle East Respiratory Syndrome (MERS) Coronavirus for which dromedaries are potential reservoirs. We are interested in the organization and diversity of immune response (IR) genes in mammals, in particular in Old World camels as their immune system and resistance to infections are very specific. Camels present a modified form of single-domain heavy-chain antibodies (IgG) that do not associate with light chains, while their V-regions are free to interact with antigens. IR genes constitute around 5% of the mammalian genome and represent a suitable model for genes that evolve under the selective pressures of pathogens. We believe that evolution and domestication have shaped the genomic regions encoding the NKR and MHC class I and II molecules due to a combination of changes in pathogen pressure and intense artificial selection. Investigating these regions will help us resolve the role of immunogenomes in evolution and domestication processes, not only in Old World camelids but also in other livestock species. Camels represent a particularly suitable model because comparisons between two domesticated species, their ancestors and a wild counterpart are possible. We will combine initial whole genome analysis and re-sequencing of selected IR genes with expression and cytogenetic studies, and investigate the evolution and differentiation of Old World camelid populations at neutral loci and loci under natural selection; including populations susceptible/ resistant to trypanosomes and MERS. We will incorporate the analysis of ancient specimens, including early-domestic and extinct wild camels, to further examine how natural selection has shaped immunogenetic diversity in camels. The characterization of the host immunogenome and its evolution will contribute to our understanding of host and pathogen interactions and the mechanisms through which infectious organisms cause disease. Defining immune response-related genes that were selected during the process of domestication will provide the basis for further marker development and marker-based selection in breeding. This will be extremely important for the growing camel milk and meat sector in (semi-) arid countries, which will have a considerable socio-economic impact. Our proposed project has a direct relevance to human health, considering that dromedaries appear to be important reservoirs of agents causing MERS.

Dromedary and Bactrian camels are important domestic animals, well adapted to harsh conditions and more resistant to devastating infections that threaten other livestock species. Infections have an important role in husbandry and in human health, such as the Middle East Respiratory Syndrome coronavirus (MERS-CoV) or the Crimean-Congo hemorrhagic fever virus (CCHFV), for which dromedaries are potential reservoirs. We were interested in the organization and diversity of immune response (IR) genes in mammals, in particular in Old World camels as their immune system and resistance to infections are very specific. Camels present a modified form of single-domain heavy-chain antibodies (IgG) that do not associate with light chains, while their V-regions are free to interact with antigens. These neutralising nanobodies can block the receptor binding domain of the SARS-CoV-2 spike protein and might provide an effective treatment against infection. IR genes constitute around 5% of the mammalian genome and represent a suitable model for genes that evolve under selective pressures of pathogens. We hypothesized that evolution and domestication have shaped the immunogenomic regions due to a combination of changes in pathogen pressure and intense artificial selection. We combined the analysis of improved whole genome assembly with in-solution hybridization capture and re-sequencing of selected IR genes, and investigated the evolution and differentiation of Old World camelid populations at neutral and adaptive IR loci; including populations infected/ non-infected with MERS-CoV and CCHFV. For both zoonotic diseases in dromedaries, we identified candidate IR genes with important functions in the adaptive and innate immune response and in cilia coating the respiratory tract. Some of these genes previously have been associated with SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia, defence in viral infections or in stimulating natural killer cells. We provide a comprehensive overview about the organisation, diversity, and evolutionary relationship of complex immunogenomic regions like the major histocompatibility complex (MHC), the leukocyte receptor complex (LRC) and the natural killer complex (NKC) in Old World camels. We could show that the overall genomics structure of these complex regions are more similar to the MHC, LCR and NKC of pigs than to those of cattle. With the characterization of the host immunogenome and its evolution we contribute to our understanding of host and pathogen interactions and the mechanisms through which infectious organisms cause disease. Defining IR-related genes provides the basis for further marker development and genomic selection in breeding. This will be extremely important for the growing camel milk and meat sector in (semi-) arid countries, which will have a considerable socio-economic impact. Our project has a direct relevance to human health, considering that dromedaries appear to be important reservoirs of agents causing MERS.