Discovery and characterization of swine host factors required to support swine influenza virus replication.

Infection of pigs with influenza viruses is a problem both for animal and human health. Swine influenza virus infections cause production losses and can predispose to more serious complications leading to loss of stock. Moreover infections of pigs by avian influenza viruses can pre-empt the emergence of a novel influenza virus that infects humans. Indeed the last influenza pandemic in 2009 had its most recent origin in pigs. Pork is an important protein source for the developed and developing world. China is a major pig producer, where pigs are reared in large holdings under sometimes crowded conditions; a perfect breeding ground for the evolution and emergence of new strains of virus. The high population in China, its geography and its climate make it a hotspot for emergence of influenza viruses. One future solution to these threats is to employ recent developments in gene editing to make a pig that is resistant to infection with influenza viruses. This is not so far-fetched; indeed, pigs resistant to another pig virus called PRRS were recently generated. However, in order to apply the breakthrough to the influenza problem we need to identify which genes in the pigs should be altered to stop the virus from being able to infect, and then define precisely how to alter them so that there is as little disruption to the meat production and breeding capacity in the edited animals.
We will identify the pig genes that are co-opted by swine influenza viruses to support their replication using a novel screening method, in pig cells with authentic swine influenza viruses typical of those circulating in China today. Then we will employ another novel screening method to work out the least changes we can make in the pig gene in order to stop the virus from infecting, because we reason this minimalistic and precise editing strategy will be the most acceptable to consumers and farmers alike.

The threat of an influenza pandemic is scored as the greatest natural-origin risk to the UK on the 2015 UK government risk register. Indeed, in a global era, the next influenza pandemic will be devastating for both developed and developing countries. Pigs are thought to be the origin or to have contributed to the origin of 3 of the 4 recent influenza pandemics. Abrogating infection of domesticated pigs by influenza viruses would alleviate this risk and thus have huge consequence on human health and economic stability around the globe.
China produces around half of the world's pigs, almost one billion animals, many farmed in large holdings. Infection of pigs with swine influenza virus causes a mild respiratory disease associated with some loss in production. But influenza infection is well known to predispose to more serious secondary infections, in pigs examples would be porcine circovirus and PRRS that lead to morbidity and mortality. The economic, agricultural and human health benefits of having pigs that cannot support influenza virus replication are obvious.
But gene editing is in its infancy, and to avoid any catastrophic unpredicted negative outcomes that could halt the advance of this exciting approach, an intelligent and well informed precise editing strategy is essential. Thus we propose to generate intelligently designed editing for pigs that could be combined with the strategy already described for PRRS to create animals resistant to two of the most prevalent swine virus diseases in China and elsewhere.