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Title: Reduced lentivirus susceptibility in sheep with TMEM154 mutations

Author
item Heaton, Michael - Mike
item Clawson, Michael - Mike
item Chitko-Mckown, Carol
item Leymaster, Kreg
item Smith, Timothy - Tim
item Harhay, Gregory
item White, Stephen
item Hoesing, Lynn
item Mousel, Michelle
item Lewis, Gregory
item KALBFLEISCH, THEODORE - University Of Louisville
item KEEN, JAMES - University Of Nebraska
item LAEGREID, WILLIAM - University Of Illinois

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2011
Publication Date: 1/26/2012
Citation: Heaton, M.P., Clawson, M.L., Chitko-Mckown, C.G., Leymaster, K.A., Smith, T.P.L., Harhay, G.P., White, S.N., Herrmann-Hoesing, L.M., Mousel, M.R., Lewis, G.S., Kalbfleisch, T.S., Keen, J.E., Laegreid, W.W. 2012. Reduced lentivirus susceptibility in sheep with TMEM154 mutations. PLoS Genetics. 8(1): e1002467. DOI: 10.1371/journal.pgen.1002467.

Interpretive Summary: Ovine lentivirus targets the host immune system and causes persistent retroviral infections affecting millions of sheep worldwide. In primates, lentivirus resistance is attributed to mutant virus coreceptors that are not expressed. In sheep, some animals are resistant to lentivirus infection despite repeated exposure; however, the mechanism of resistance is unknown. We designed a genome-wide association study to test whether sheep might have mutant genes that protect against lentivirus infection. Our results showed that variation in an ovine gene (TMEM154) was associated with infection. Sheep with the ancestral type of this gene were nearly three times more likely to become infected than those with mutant forms. We also discovered three mutant forms predicted to abolish the protein's function. Although the biological function of TMEM154 is unknown, our results indicate that it plays an important role in lentivirus infection in sheep. Producing sheep with the least susceptible form of TMEM154 may help eradicate the ovine disease caused by lentivirus.

Technical Abstract: Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the U.S., is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Matched pairs of infected cases and uninfected controls were identified among 3,545 sheep and used in a genome-wide association study. One single nucleotide polymorphism (SNP) in the ovine transmembrane protein (TMEM154) exceeded genome-wide significance (adjusted p-value 1.6 x 10**-**4). The ovine TMEM154 coding region contained five missense and three frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection, while a third haplotype with lysine (K) at position 35 was not. The E35 haplotypes were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 130 naturally exposed pairs of ewes. The odds of infection for ewes with one copy of a TMEM154 E35 allele were 69 times greater than the odds for those without (p-value <0.0001, 95% CI 12-2,800). In a combined analysis of cohorts from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.71 times greater for sheep with a full-length TMEM154 E35 allele (p-value <0.0001, 95% CI 2.33-3.14). Although rare, some sheep carried homozygous TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection, and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.