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Diversity of β-retroviruses causing respiratory cancers in small ruminants
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International audience. ENTV (Enzootic Nasal Tumor Virus) and JSRV (Jaagsiekte Sheep Retrovirus) are β-retroviruses inducing respiratory cancers. JSRV infects sheep, ENTV-1 and ENTV-2 respectively infect sheep and goats. These viruses and the induced cancers are endemic in many countries and the disease can be observed as isolated cases or as disease outbreaks. The envelope (Env), specifically the intracytoplasmic domain of the transmembrane glycoprotein, is oncogenic, transforming cells in vitro and in vivo.We analyzed the genetic features of the sheep and goat β-retrovirus (29 JSRV and 23 ENTV-2 strains) circulating in France to identify molecular signatures linked to the severity of the disease in given flocks. We focused on the env gene, encoding the oncogenic viral envelope, and on the LTR (Long Terminal Repeat), the non-coding region of the integrated provirus controlling viral replication. As in other mammals, multiples copies of β-endogenous retroviruses resulting from ancestral infections of germinal cells during evolution, are present in the small ruminants genomes. As endogenous and exogenous retroviruses are genetically highly related (over 95 % of nt sequence similarity), a highly specific strategy had to be developed to selectively amplified the exogenous ENTV and JSRV genomes, based on limited discriminating motifs along their genomes. As an intern quality control, all the ENTV-2 and JSRV sequences displayed a YXXM motif in the cytoplasmic tail of the transmembrane protein coding sequence, described as an Akt docking motif involved in cell transformation and oncogenicity, known as a specific feature of the exogenous β-retroviruses.Based on French isolates, ENTV-2 strains were globally less diverse (0.4% nucleotide variability) than JSRV strains (4.8%). Longitudinal study in JSRV infected flock showed highly stable strains with no env and LTR variability over the course of 4 years. For 8/9 flocks studied with several samples available, the nucleotide variability of env was below 1.5% highlighting a high genomic stability of the viruses within a flock. The phylogenetic reconstruction based on the LTR and env regions are suggesting that a major strain is circulating on the French territory for ENTV-2 while not clustering with already published Spanish nor Chinese strains. On the contrary, JSRV strains circulating in French ovine flocks were distributed in 2 distinct genetic subtypes, clustering with already published sequences originated from North America, Africa and United-Kingdom. Specific motifs in the LTRs and in the intracytoplasmic domain of the envelope were spotted between the two genetic subtypes. In the U3 region of the LTR, sequences associated with JSRV cancer outbreaks showed a duplication of the CREB binding site, involved in modulating transcription, and the presence of an E2F-1 binding site, involved in modulating cell proliferation. Their impact on disease severity remains to be established. Ongoing sequencing of the entire provirus will complete the analysis by investigating the diversity of gag pro and pol genes among the different strains.This is the first report on French strains of oncogenic β-retroviruses responsible for cancers in sheep and goats. We identified genetic signatures associated with severity of disease that will be tested for the oncogenic properties in an in vitro system.
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