Genetic and splice variations of CD46 shift cell permissivity to BVDV, the bovine pestivirus

Hussein Zezafoun (1) , Annabelle Decreux (1) , Daniel Desmecht (1)

1 Faculty of Veterinary Medicine

The pestivirus bovine viral diarrhea virus (BVDV) is known to bind to the CD46 molecule, which subsequently promotes entry of the virus. Mapping of the BVD-virion-binding site has shown that two peptides, 66EQIV69 and 82GQVLAL87, located on antiparallel beta sheets in the most distal complement control protein module (CCP1), provide the attachment platform. In the present study, we reveal the existence of ten distinct allelic versions of the CCP1 module, varying significantly in frequency among taurine and indicine races. A complex mRNA splicing pattern was also evidenced for bovine CD46, generating three different serine-threonine-proline segments and five different cytoplasmic domains. The four most frequent allelic variants and the six splice variants were then expressed in BVDV-nonpermissive porcine cells and the quantity of progeny virions generated by each cell preparation was measured 48hours post-infection. As expected, ectopic expression of the 10 bovine CD46 isoforms rendered the PK15 cells permissive to BVDV, as attested by the 100,000-fold greater recovery of virions from these cells than from non-transfected cells. This permissivity increase was significantly lower (-33%, P<0.001) when the canonical CCP1 was replaced with the variant most frequent in zebus, suggesting positive or negative selection of this allele in the latter and in the former, respectively. The predicted secondary structure of this variant suggests that the measured loss of function is due to the disappearance of one of the two beta sheets constituting the BVDV attachment platform. On the other hand we showed that for a given CCP1, the titer recovered at 48 hpi also depended on the nature of the CD46 cytoplasmic domain (P<0.001). This result implies that virus binding generates a cytoplasmic-tail-dependent ouside-in signal that determines permissivity to BVDV.

Mots clés: CD46; Bos Taurus; BVD/MD; polymorphism

Domaines: Médecine vétérinaire et santé animale

Hussein Zezafoun, Annabelle Decreux, Daniel Desmecht. Genetic and splice variations of CD46 shift cell permissivity to BVDV, the bovine pestivirus. Veterinary Microbiology, 2011, 152 (3-4), pp.315. ⟨10.1016/j.vetmic.2011.05.028⟩. ⟨hal-00724198⟩