Primary Cells from a <i>CD46</i>-Edited Bovine Heifer Have Reduced BVDV Susceptibility Despite Viral Adaptation to Heparan Sulfate

Primary Cells from a <i>CD46</i>-Edited Bovine Heifer Have Reduced BVDV Susceptibility Despite Viral Adaptation to Heparan Sulfate

A precision genome edit in the bovine <i>CD46</i> gene (A<sub>82</sub>LPTFS<sub>87</sub>) dramatically reduced bovine viral diarrhea virus (BVDV) susceptibility in a cloned heifer. However, pathogen evolution threatens the long-term efficacy of such interventions....

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Bibliographic Details
Main Authors: Alexandria C. Krueger, Brian L. Vander Ley, Michael P. Heaton, Tad S. Sonstegard, Aspen M. Workman
Format: Article
Language:English
Published: MDPI AG 2025-04-01
Series:Viruses
Subjects:
bovine viral diarrhea virus
BVDV
cattle
CD46
gene editing
heparan sulfate
Online Access:https://www.mdpi.com/1999-4915/17/5/634
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Summary:A precision genome edit in the bovine <i>CD46</i> gene (A<sub>82</sub>LPTFS<sub>87</sub>) dramatically reduced bovine viral diarrhea virus (BVDV) susceptibility in a cloned heifer. However, pathogen evolution threatens the long-term efficacy of such interventions. Here, our aim is two-fold: first, to determine whether BVDV can adapt in vitro to use the edited CD46 receptor to infect Madin–Darby bovine kidney (MDBK) cells, and second, to evaluate the ex vivo infectivity of culture-adapted viruses in cells from the <i>CD46</i>-edited heifer. Serial passage of BVDV on <i>CD46</i>-edited MDBK cells selected for virus variants capable of CD46-independent infection. Virus genome sequencing revealed mutations in the viral E<sup>RNS</sup> gene predicted to enhance HS-mediated entry. HS adaptation was confirmed by inhibiting virus infection with heparin or Heparinase I/III treatment. A naturally occurring HS-adapted field isolate from a persistently infected calf showed similar results. However, when tested on primary cells from the <i>CD46</i>-edited heifer, HS-adapted viruses showed reduced infectivity in skin fibroblasts, monocytes, and lymphocytes in a manner that correlated with HS expression. Thus, although BVDV can adapt to use HS as an alternative entry receptor, HS adaptation does not overcome the protection conferred by the <i>CD46</i> edit in all relevant cell types.
ISSN:1999-4915

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