In a new study, researchers have identified a protein in mammals that welcomes arteriviruses into host cells to trigger infection. The team also discovered that an existing monoclonal antibody that binds to this protein protects cells against viral infections.

Arteriviruses circulate widely in many types of mammals around the world that serve as natural hosts – such as non-human primates, pigs and horses – but have so far not been detected in humans.

The researchers’ goal is to better understand the mechanisms of arterivirus infection to determine the level of infection risk to humans and the preparation that might be needed in the event of a future spillover.

“It is important to consider that since we have no known arteriviruses infecting people, we are essentially immunologically naive, so we cannot rely on pre-existing immunity to help us,” said co-senior author Cody Warren, assistant professor of veterinary biosciences at The Ohio State University.

Warren co-led the work with Adam Bailey, assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison. The study was recently published in Natural communications.

Many natural arterivirus hosts show no signs of disease, but the virus that infects pigs can cause pneumonia, as well as abortions in pregnant piglets, and other strains can cause hemorrhagic fever or encephalitis when they change animal hosts.

These viruses also have the unusual ability to maintain long-term infections and become more virulent when they find new hosts, giving them time to evolve and improve their chances of transmission.

The research team sought to find proteins in mammals that arteriviruses use as receptors to enter host cells and reproduce. Bailey used genome-wide CRISPR-knockout screening technology to identify specific genes that, when disrupted, made cells resistant to viral infection. Such genes would then be considered essential to the viral infection process. The unbiased analysis identified two genes, FCGRT And B2Mwhose protein products assemble to form the FcRn receptor (neonatal Fc receptor) which is expressed on the surface of cells.

The FcRn receptor molecule plays a specific role in transporting antibodies across the placenta to the fetus, but it is also present in immune cells and cells that line the walls of blood vessels, both of which are targeted by arteriviruses.

The results of this study demonstrated that FcRn is used for entry into host cells by at least five arteriviruses that infect monkeys, pigs, and horses, respectively: three diverse strains of simian arterivirus, reproductive syndrome virus and porcine respiratory virus 2 (PRRSV-2) and equine virus. arteritis virus (EAV).

By eliminating the major component of the FcRn complex — the FCGRT gene – from host cells blocked by viral infection and pretreating the cells with a monoclonal antibody against FcRn protected against infection.

There was also a genetic twist to this story: Some mammalian hosts were less susceptible to arterivirus infection due to differences in their species-specific FcRn sequence, meaning that in some cases this protein will function as a barrier against infections between species.

“Chimpanzees and humans have roughly the same genes, but the sequence of those genes is slightly different,” Bailey said. “All mammals have the FcRn receptor, but their ability to withstand infection with a given arterivirus can vary.”

The CRISPR screen also identified a gene encoding another surface protein, CD163, which Warren and colleagues previously discovered was a gatekeeper for an arterivirus called simian hemorrhagic fever virus (SHFV) to infect a cell.

A series of experiments on different cell types and using multiple virus strains in the new study showed that CD163 does indeed play a role in infection by most arteriviruses, but it cannot act alone. Interaction with FcRn is also essential to facilitate arteriviral infection of host cells. .

Defining these stages of arterivirus infection is an important step, the researchers said.

“If we look at the biology of viruses, one of the most important things we can understand is entry mechanisms. Because if you can stop a virus’s ability to infect a cell by disrupting that initial virus contact -receptor, you now have a potential therapeutic strategy,” Warren said.

One of these “disruptors” could block the receptor – so showing that an existing monoclonal antibody can stop viral infection in cells is also a plus for scientists examining viruses as part of a pre-preparation process. pandemic.

“If any of these viruses appeared in humans, I think we would be in big trouble,” Bailey said. “So that’s what motivates me.”

This work was supported by grants from the National Institutes of Health, seed funds from the University of Wisconsin-Madison, the G. Harold and Leila Y. Mathers Foundation, and the Burroughs Wellcome Fund Pathogenesis of Infectious Disease Program.

Co-authors included Teressa Shaw, Kylie Nennig, Xueer Qiu, Devon Klipsic and Igor Slukvin of UW-Madison; Devra Huey, Makky Mousa-Makky, Jared Compaleo, Fei Jiang and Haichang Li of Ohio State; Aadit Shah of Stanford University; Raymond Rowland of the University of Illinois Urbana-Champaign; and Meagan Sullender and Megan Baldridge of Washington University in St. Louis.