Eugenic selection assisted by a BoLA-DR/DQ haplotype associated with susceptibility to bovine dermatophilosis

Dermatophilosis is a severe skin infection of tropical ruminants inducing a loss in productivity and a 15% mortality rate. This disease is due to the actinocyces Dermatophilus congolensis associated with the tick Amblyomma variegatum. Currently, no vaccine is expected and chemoresistance phenomena decrease the means of control (acaricides and antibiotics). Breeders observed that the disease seemed to be controlled by genetic determinism. Based on an 8 year-Iong ecopathological survey of 568 zebu Brahman cattle from several herds located in Martinique Island (FWI), we classified into two extreme groups 123 unrelated animals of both sexes, reared in the same environmental conditions. The most resistant individuals (n=61) were never infected whereas the susceptible individuals (n=62) showed severe clinical signs and later died. Using a functional candidate gene approach we studied the DNA polymorphisms of several targeted genes (macrophage lysosyme, Nramp1, TNF alpha, lymphotoxin, MHC class I and class II molecules (BoLA-DRB3 and DQB) and TcR-CD3) encoding molecules implicated in known mechanisms of both non-specific and specific immune responses. The most significant results were obtained within the Major Histocompatibility Complex (MHC) where the BoLA-DRB3 and DQB genes encode molecules involved in the pathogen/host interface mechanisms, particularly in the antigen presentation to T cell receptors. Firstly in the highly polymorphic BoLA-DRB3 exon 2 encoding the antigen binding groove, we found a particular CESFLQKN amino, acids sequence present in the 5 official alleles DRB3.2*0301, *0302, *0901, *0902, and *1202, which correlates with the susceptibility. On the other hand, we found another strong correlation between susceptibility and the BoLA-DQB*1804 allele. Finally, the most interesting observation is the strong linkage of both previous DRB3.2 and DQB alleles in a unique particular BoLA class II haplotype, which constitutes a highly significant marker (P<0.0001) of susceptibility to bovine dermatophilosis. This haplotype marker of susceptibility was also found and validated in other bovine populations either of the same breed (Brahman zebu of Madagascar) or of different breeds (in Cameroon, Burkina Faso and Guadeloupe (FWI)). A eugenic marker assisted selection was developed in the field by eliminating the animals with this haplotype of susceptibility, and the disease prevalence was reduced from 0.76 to 0.06 over 5 years. On the other hand, the BoL4-DRB3.2*4201 linked to the DQB*1805 constitutes a haplotype correlating with the resistance character (P<0.001). Based on these BoLA DRB3/DQB haplotypes, F1 crossbreeding plans are in progress to study the genetic transmission of the genotypic and phenotypic characters of dermatophilosis resistance and susceptibility. In conclusion, we discuss several hypothesis at the molecular and cellular levels to better define the exact role of the MHC molecules in diseases control and to answer the questions: how MHC diversity is selectively maintained by natural selection imposed by the pathogens, how in concrete terms, could such results be pratically applied in integrated controls in developing countries and finally what could be the new ways of research to be developed in the future. (Texte intégral)