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Genome Editing Builds Viral Disease Resistance in Pigs

Piglets

(Laura Dow, Roslin Institute)

24 February 2017. Veterinary researchers used Crispr-Cas9, an emerging genome editing technique, to produce pigs with cells resistant to a common viral disease affecting commercial herds. The team from Roslin Institute at University of Edinburgh in Scotland and Pirbright Institute in Woking, U.K., and the livestock breeding company Genus plc in Basingstoke, U.K. published its findings in the 23 February issue of the journal PLoS Pathogens.

The researchers led by Roslin Institute geneticist Alan Archibald are seeking solutions to porcine reproductive and respiratory syndrome, or PRRS, a viral disease that began affecting pig herds in Europe and North America in the late 1980s. Infections from the virus cause lesions in the lungs of young pigs and severe respiratory distress, with fatalities at this age as high as 80 percent. Among pregnant sows, infections can cause stillbirths of entire litters and early terminations of pregnancies. The authors cite data showing pork producers in the U.S. suffering annual losses of $650 million from PRRS, and more than €1.5 billion in Europe.

The PRRS virus infects macrophages, white blood cells in the immune system that normally attack and absorb invading pathogens. In this case, the virus attacks the macrophage itself, seeking out and binding to a receptor protein known as CD163, often found in the lung macrophages of pigs. That protein has a molecular structure resembling a string of pearls, where the fifth “pearl”  or region in the sequence interacts with the PRRS virus, enabling infections to occur.

Archibald and colleagues investigated the genome editing technique known as Crispr, short for clustered regularly interspaced short palindromic repeats, as a technique for changing the gene in pigs that produces CD163. Crispr is based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr uses an enzyme known as Crispr-associated protein 9 or Cas9. With this approach to Crispr, RNA molecules guide Cas9 proteins to specific genes needing repair, making it possible to address root causes of many diseases.

The researchers identified the gene and specific exons, or parts of the gene, in pigs that direct the RNA code for producing CD163 proteins. Using Crispr-Cas9, the team deleted only the precise exon in pig zygotes with the code for the fifth region in CD163 proteins. The zygotes were then implanted in sows and proceeded to birth. The team reports the pigs experienced normal births and were raised under standard care and conditions, with no adverse effects and normal blood counts.

Lab tests of macrophages from the lungs of the gene-edited pigs show normal functioning of CD163 proteins on the macrophage surface, even with the fifth coding region removed. The researchers then exposed the pigs’ macrophages to various types of PRRS viruses and found that the cells resisted infections, resulting from the lack of receptor protein normally found in pigs’ macrophages, but edited out with Crispr-Cas9.

“Genome-editing offers opportunities to boost food security,” says Archibald in a joint statement, “by reducing waste and losses from infectious diseases, as well as improving animal welfare by reducing the burden of disease. Our results take us closer to realizing these benefits and specifically address the most important infectious disease problem for the pig industry worldwide.”

The next stage in the research is to test the resistance of pigs with edited genomes to infections from PRRS viruses, not just the macrophage cells.

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