Porcine Reproductive and Respiratory Syndrome (PRRS) virus is the most economically damaging virus for global pork production, responsible for approximately $600 million in annual losses for American pig farmers alone.
The virus first emerged in North America in 1987 and does not yet have a widely effective vaccine or cure. However, University of Connecticut assistant professor of animal science Young Tang and Antonio Garmendia, professor of pathobiology and veterinary science, have now successfully identified compounds that can effectively block the virus from infecting pig cells, creating a promising pathway to an alternative treatment. They published their findings in the most recent edition of Virology Journal.
The PRRS virus is highly contagious and affects both young and adult pigs. The virus causes a respiratory disease, usually affecting young pigs, and a reproductive form affecting pregnant sows, which leads to abortions, stillbirth, and infertility. The virus also severely weakens the pig’s immune system, making it more susceptible to other infections.
The UConn research team identified a cell surface receptor called CD163 that is expressed in pig monocytes and macrophages that the virus needs to get into the pig target cells, and hypothesized that a small molecule blocking this receptor would block infection.
In collaboration with Atomwise, a biotechnology company in San Francisco, Tang and Garmendia used artificial intelligence (AI) technology to virtually screen millions of compounds and identify small molecules that could block CD163. After identifying the best candidates, Atomwise sent Tang and Garmendia 74 small molecules predicted to have the highest potential of targeting the receptor to test in their labs.
The UConn researchers then used a bimolecular fluorescence complementation (BiFC) assay to determine if the compounds could block the viral glycoproteins from interaction with the cell receptor. When proteins interact, they generate fluorescence in the assay, which, in this case, indicates the viral glycoprotein binds to the receptor. When the researchers did not observe fluorescence, this meant the small molecule successfully blocked the virus.
They found that one of the predicted compounds, named B7, blocked the formation of fluorescence in the BiFC assay. In follow-up assays, they determined that B7 blocked the virus infection of pig cells, becoming the very first in vitro study demonstrating successful inhibition of viral receptor recognition by the PRRS virus.
There are many strains of the PRRS virus, making attempts to create broadly protective vaccines very challenging. Vaccines work by spurring the body to produce antibodies specific for the strain of virus used as the vaccine. Because the virus mutates so quickly and has so many strains, it is impossible to vaccinate pigs against every variant.
The researchers tested the small molecules from Atomwise with both the American and European types of the virus and found that B7 effectively blocks both. These two types are genetically diverse, making this finding’s broad applicability significant.
Coupled with existing vaccines, this compound would provide a second line of defense against PRRS. While vaccines prompt the creation of antibodies, the small molecule would block the virus’ attachment to cell receptors, reducing further virus shedding and transmission.
“This would protect animals better than a vaccine alone,” Garmendia says. “It could have a significant impact.”
The research collaboration also identified several B7 analogs that produced similar results. By identifying these analogs with similar structures, the researchers gleaned a better idea of which of several chemical groups on B7 were responsible for disrupting the viral infection.
With support from UConn Technology Commercialization Services, the researchers have filed a provisional patent for this advancement and are actively seeking industry partners.
“Hopefully we’ll find industry collaborators to develop this technology further and invest in this area,” Tang says.
The next step for this research is to perform in vivo experiments to further test the effectiveness of these small molecules in infected pigs.
“If we find it can be as effective in vivo as it is in vitro with low toxicity to the pigs, we can say we’ve found a cure for this disease,” Tang says.
If a cure is developed, it would be a boon for pork farmers. Farmers could sell PRRS-free pigs, something that is currently rare, while saving a tremendous amount each year by reducing the incidence of the illness.