Deciphering the mechanisms of rabbit genetic resistance to myxomatosis and rabbit haemorrhagic viral disease

Infectious diseases are thought to play a major role in shaping the genetic diversity of host organisms. The European rabbit (Oryctolagus cuniculus) is a remarkable species in the sense that has been affected by two major viral diseases in the last fifty years: myxomatosis and the rabbit haemorrhagic disease (RHVD). The first is now a text-book example of host-pathogen evolution and is caused by the myxoma virus, a member of the genus Leporipoxvirus that is most commonly transmitted by mechanical transfer through insect bite. On the other hand, RHVD is caused by a calicivirus that is disseminated by direct contact or mechanically transmitted through insects.Development of both diseases results from a complex interaction between the parasite, the host and the environment. In the last few years, detailed studies of rabbit numbers in different countries showed a clear increase in the genetic resistance to both diseases, leading to the hypothesis that rapidly expanding protective genetic variants may be associated to the recovery of natural populations. Recently, candidate genes that confer resistance to myxomatosis and RHVD have been proposed. The myxoma virus uses a variety of members of the chemokine receptor superfamily for cell binding and entry in order to initiate the infectious process. While CCR1, CCR5 and CXCR4 were certainly among the candidate chemokines involved in resistance to myxomatosis, a remarkable similarity in the process of how CCR5 is used for cell entry by both the AIDS virus in humans and the myxoma virus in rabbits was described. For RHVD, the ability of the virus to attach to rabbit epithelial cells of the upper respiratory and digestive tracts has been shown to depend on the presence of ABH blood group antigens. The genes that control the synthesis of H antigens in erythrocytes and saliva are the alpha-1,2 fucosyltransferase genes FUT 1, FUT 2 and Sec1.

This project aims to understand the role of these specific genes in the increasing resistance of wild rabbit populations to two of the most devastating but also more investigated and better documented wildlife diseases ever described. We will take advantage of our in-depth knowledge of the evolutionary history of wild rabbit populations that we have previously addressed through the study of multiple genetic markers. In addition, we will also have the possibility of using wild rabbit populations introduced a few centuries ago in remote Atlantic islands that were never affected by both diseases. By using this unique combination of a very well characterized evolutionary and demographic history together with a detailed molecular analysis of six candidate genes for resistance to both myxomatosis and RHVD, we expect to provide undisputable evidence for a recent role of natural selection in determining the present-day patterns of diversity at these loci.