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Abstract :
[en] Alcelaphine herpesvirus 1 (AlHV 1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (MCF) when cross species transmitted to a variety of susceptible species of the Artiodactyla order. There is no available vaccine against AlHV-1. Several studies suggested that the African buffalo (Syncerus caffer) rather than cattle should be considered as the natural host species of bovine herpesvirus 4 (BoHV 4), an apathogenic gammaherpesvirus that is antigenically related to AlHV 1. Rossiter and co-workers (1989) suggested that an evolutionary relationship exists between AlHV 1 and BoHV 4. This hypothesis proposes that the serological antigenic relationship existing between BoHV 4 and AlHV 1 could confer to BoHV 4 infected buffaloes a protective immune response against lethal AlHV 1 infection. In this work, our goal was to generate information and tools that are required to test this hypothesis in the future. Our results are presented as three original studies:
(i) Cloning of the alcelaphine herpesvirus 1 genome as an infectious and pathogenic bacterial artificial chromosome
Journal of General Virology (2005), in press
Dewals B., Boudry C., Gillet L, Markine-Goriaynoff N., de Leval L., Haig D.M. & Vanderplasschen A.
Alcelaphine herpesvirus 1 (AlHV 1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (MCF) when cross species transmitted to a variety of susceptible species of the Artiodactyla order. The study of MCF pathogenesis has been impeded by an inability to produce recombinant viruses, due mainly to the fact that AlHV 1 becomes attenuated during passage in culture. In this study, we have overcome these difficulties by cloning the entire AlHV 1 genome as a stable, infectious and pathogenic bacterial artificial chromosome (BAC). A modified loxP flanked BAC cassette was inserted in one of the two large non-coding regions of the AlHV 1 genome. This insertion allowed the production of an AlHV 1 BAC clone stably maintained in bacteria and able to regenerate virions when transfected into permissive cells. The loxP-flanked BAC cassette was excised from the genome of reconstituted virions by growing them in permissive cells stably expressing Cre recombinase. Importantly, BAC derived AlHV 1 virions replicated comparably to the virulent (low passage) AlHV 1 parental strain and induced MCF in rabbits that was indistinguishable from that of the virulent parental strain. The availability of the AlHV 1 BAC is an important advance for the study of MCF that will allow the identification of viral genes involved in MCF pathogenesis as well as the production of attenuated recombinant candidate vaccines.
(ii) Antibodies against bovine herpesvirus 4 are highly prevalent in wild African buffaloes throughout eastern and southern Africa
Veterinary Microbiology, 2005, 110, 209-220
Dewals B., Gillet L., Gerdes T., Taracha E.L.N., Thiry E. & Vanderplasschen A.
Bovine herpesvirus 4 (BoHV 4) has been isolated from cattle throughout the world. Interestingly, a survey of wild African buffaloes mainly from the Maasai Mara Game Reserve in Kenya revealed that 94 % of the animals tested had anti BoHV 4 antibodies (Rossiter et al., Res. Vet. Sci., 1989, 46, 337 343). These authors also proposed that the serological antigenic relationship existing between BoHV 4 and alcelaphine herpesvirus 1 (AlHV 1) could confer to BoHV 4 infected buffaloes a protective immune response against lethal AlHV 1 infection. In the present study, we addressed two questions related to Rossiter et al. paper. Firstly, to investigate the role of the African buffalo as a natural host species of BoHV 4, the seroprevalence of anti BoHV 4 antibodies was analysed in wild African buffaloes throughout eastern and southern Africa. A total of 400 sera was analysed using two complementary immunofluorescent assays. These analyses revealed that independently of their geographical origin, wild African buffaloes exhibit a seroprevalence of anti BoHV 4 antibodies higher than 68 %. This result is by far above the seroprevalence generally observed in cattle. Our data are discussed in the light of our recent phylogenetic study demonstrating that the BoHV 4 Bo17 gene has been acquired from a recent ancestor of the African buffalo. Secondly, we investigated the humoral antigenic relationship existing between BoHV 4 and AlHV 1. Our results demonstrate that among the antigens expressed in AlHV 1 infected cells, epitope(s) recognized by anti BoHV 4 antibodies are exclusively nuclear, suggesting that the putative property of BoHV 4 to confer an immune protection against AlHV 1 relies on a cellular rather than on a humoral immune response.
(iii) Phylogenetic analysis of Bovine herpesvirus 4 strains isolated from cattle and from African buffalo
In preparation
Dewals B., Thirion M., Markine-Goriaynoff N., Gillet L., de Fays K., Minner F., Daix V., Sharp P.M. & Vanderplasschen A.
Bovine herpesvirus 4 (BoHV 4) is a gammaherpesvirus which has been isolated from cattle throughout the world. Virological and serological studies have demonstrated that the African buffalo is also a natural host species of BoHV-4. Interestingly, our phylogenetic study on the BoHV 4 Bo17 gene revealed that this gene has been acquired from an ancestor of the African buffalo around 1.5 million years ago. Study of the Bo17 gene also suggested a relatively ancient transmission of BoHV-4 from the ancestor of the African buffalo to the Bos primigenius lineage, followed by a host-dependent split between zebu and taurine BoHV-4 strains. In the present study, we pursued our investigations on the evolution of BoHV 4. To investigate the phylogenetic relationship existing between BoHV 4 strains isolated from African buffalo in Kenya and from cattle throughout the world, nine strains representative of the BoHV 4 species were compared based on six different regions distributed across the genome. Our phylogenetic analyses led to the following conclusions: (i) BoHV 4 strains from African buffalo and from cattle form clades which have split approximately 700,000 years ago. (ii) Since this divergence, inter clade and intra-clade recombination events occurred at different time in the past. (iii) the topology of the tree formed by zebu and taurine BoHV 4 strains is incompatible with a co-speciation process between BoHV 4 and domestic cattle implying that the latter have been contaminated through recent cross-species transmission. A scenario is proposed to explain how BoHV 4 has been transmitted from African buffalo to cattle and how the virus has reached a world wide distribution in the latter host species.
In conclusion, this work generated key information and reagents to test in a near future the hypothesis proposed by Rossiter et al. (1989). The results of this work show the complexity of the interactions existing between viruses and their hosts throughout evolution.
