While porcine reproductive and respiratory syndrome (PRRS) virus first emerged in North America in 1987, the virus remains one of the most persistent and costly disease complexes affecting the U.S. swine industry.
University of Connecticut assistant professor of animal science Young Tang and professor of pathobiology and veterinary science Antonio Garmendia have now successfully identified compounds that can effectively block the virus from infecting pig cells, creating a promising pathway to an alternative treatment, according to an announcement from the University of Connecticut. They recently published their findings in Virology Journal.
The PRRS virus is highly contagious and affects both young and adult pigs. The virus causes a respiratory disease that usually affects young pigs, and a reproductive form affects pregnant sows, leading to abortions, stillbirths and infertility. The virus also severely weakens the pig’s immune system, making it more susceptible to other infections.
The Connecticut research team hypothesized that a small molecule blocking a cell surface receptor called CD163 — which is expressed in pig monocytes and macrophages that the virus needs to get into the pig target cells — could block infection.
(Note that CD163 has been the target of research aiming to breed pigs genetically resistant to PRRS virus.)
In collaboration with Atomwise, a biotechnology company in San Francisco, Cal., Tang and Garmendia used artificial intelligence technology to virtually screen millions of compounds and identify small molecules that could block CD163, the announcement from the university said. 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 Connecticut researchers 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 that 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 from infecting pig cells, becoming the very first in vitro study to demonstrate successful inhibition of viral receptor recognition by the PRRS virus, the university reported.
There are many strains of the PRRS virus, which makes it challenging to create broadly protective vaccines, the researchers said.
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, the announcement said.
Coupled with existing vaccines, this compound could provide a second line of defense against PRRS, the researchers said, adding that while vaccines prompt the creation of antibodies, the small molecule would block the virus’s attachment to cell receptors, reducing further virus shedding and transmission.
“This would protect animals better than a vaccine alone,” Garmendia said. “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 said.
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 said.
