A New Understanding of Viral Infection

Scientists researching animal viruses with the potential to infect humans have identified a crucial protein that could facilitate the spread of arteriviruses—a family of viruses present in various mammals.

In a recent study, researchers discovered a protein in mammals that enables arteriviruses to enter host cells and begin infection. They also found that an existing monoclonal antibody binding to this protein could protect cells from viral infection.

Although arteriviruses have not yet been detected in humans, they are common in animals like pigs, horses, and nonhuman primates, which serve as their natural hosts.

The researchers aim to deepen their understanding of arterivirus infection mechanisms to assess the risk of human infection and necessary preventive measures. 

“We have no known arteriviruses infecting people, so we’re essentially immunologically naïve; we can’t rely on preexisting immunity to help us,” explains Cody Warren, co-lead author and assistant professor of Veterinary Biosciences at The Ohio State University.

The study, co-led by Adam Bailey, an assistant professor at the University of Wisconsin-Madison, was published in Nature Communications.

Certain arteriviruses, such as the swine virus, can cause pneumonia and miscarriages in pregnant pigs. Other strains may cause hemorrhagic fever or encephalitis when they cross into new animal hosts. While many animals naturally hosting arteriviruses show no symptoms, these viruses can sustain long-term infections and evolve to become more virulent when infecting new hosts, increasing their potential for spread.

The study aimed to identify proteins in mammals that serve as receptors for arteriviruses, allowing viral entry and replication in host cells. Using genome-wide CRISPR knockout screening, Bailey pinpointed genes that, when disrupted, rendered cells resistant to infection. Two such genes, FCGRT and B2M, produce proteins that combine to form the neonatal Fc receptor (FcRn), which is present on the cell surface.

Arteriviruses target immune cells and cells lining blood vessels, both containing the FcRn receptor, which also transports antibodies from mother to fetus. The study showed that at least five arteriviruses—including equine arteritis virus (EAV), porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), and three simian arteriviruses—use FcRn to enter host cells.

Disrupting the FCGRT gene blocked viral infection in host cells, and pre-treating cells with an antibody against FcRn prevented infection. The study further revealed that genetic variations in the FcRn receptor across species can influence susceptibility to arteriviruses, suggesting that FcRn could act as a barrier to cross-species infections.

“All mammals have the FcRn receptor, but its sequence differs slightly between species, potentially affecting the likelihood of infection with a specific arterivirus,” says Bailey.

The CRISPR screen also identified CD163, a gene encoding another surface protein Warren and colleagues had previously shown to facilitate arterivirus entry. The study confirmed that although CD163 plays a role in infection, interaction with FcRn is also crucial for arteriviral infection of host cells.

According to the researchers, defining these stages of arterivirus infection is essential. “Understanding entry mechanisms is vital,” Warren notes. “If we can prevent the virus from entering a cell by disrupting this initial contact, we open the door to potential therapies.”

For scientists focused on pre-pandemic preparedness, proving that a monoclonal antibody can prevent arterivirus infection in cells is a promising discovery, as one of these disruptors might prevent receptor binding in humans.

“If one of these viruses emerged in humans, we’d be facing a major challenge,” Bailey adds, underscoring the importance of their work.