Association of TMEM154 variants with visna/maedi virus infection in Turkish sheep

Abstract

Visna/maedi (VM) is a multisystemic disease of sheep characterized by persistent lentiviral infection, slow progression and eventually death. The VM virus (VMV) affects sheep throughout the world and is the focus of national eradication campaigns. A major host gene associated with infection has been identified in North American sheep (TMEM154); however, its effect is unknown in Turkish sheep. Our aim was to determine VMV seroprevalence in naturally infected Turkish sheep, characterize their TMEM154 alleles, and test for association with infection. A 2017 serological census was taken of 2266 ewes from 11 flocks, at six locations, comprising seven native and four composite Turkish breeds. VMV serum antibodies were measured with an enzyme linked immunosorbent assay. Eight of 11 flocks were infected with VMV (2 to 83% seroprevalence). TMEM154 variants were typed by sequencing exon 2 from all 287 seropositive ewes and a subset of their seronegative flockmates (1059 total). TMEM154 sequencing revealed five of 12 known haplotypes encoding missense mutations, and one previously unreported variant (G38R) in Kivircik sheep. VMV seroprevalence in ewes with highly-susceptible TMEM154 haplotypes (full length E35 variants) was higher than the overall flock seroprevalence and independent of breed type. Genetic association was tested in 76 matched case-control pairs from 751 comingled ewes from a research flock. Pairwise analyses showed the risk of infection was 3-fold greater for ewes with one or two copies of highly-susceptible TMEMI54 haplotypes compared to those with combinations of K35 and deletion variants (CI95 1.3-8.7, p-value 0.009). Allelic combinations of TMEM154 K35 and deletion variants had an apparent protective effect against VMV strains in Turkish sheep. The low frequencies of K35 and deletion alleles in native Turkish breeds suggests selective breeding may help reduce the seroprevalence in affected flocks and decrease the risk of outbreaks in VMV-free flocks.