New findings on animal viruses that can potentially infect humans

In a new study, researchers identified a protein in mammals that welcomes arteriviruses into host cells to initiate an 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 species of mammals around the world that serve as natural hosts – such as non-human primates, pigs and horses – but have not yet been detected in humans.

The researchers’ goal is to better understand the mechanisms of arterivirus infection to get a handle on how high the risk of infection is for humans and what preparation may be needed if a spillover occurs in the future.

“It’s important to remember that because we don’t know that arteriviruses infect humans, we are essentially immunologically naïve, so we can’t rely on pre-existing immunity to help us,” said co-lead author Cody Warren, assistant professor veterinary biosciences at The Ohio State University.

Warren led the work along with Adam Bailey, assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison. The research was recently published in Nature communication.

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

These viruses also have the unusual ability to maintain long-lasting infections and become more virulent as they find new hosts – giving them time to evolve and increase their chances of transmission.

The research team looked for proteins in mammals that arteriviruses use as receptors to gain access to host cells and make copies of themselves. Bailey used genome-wide CRISPR knockout screening technology to identify specific genes that, when disrupted, made cells resistant to viral infections. Such genes would then be considered essential for the viral infection process. The unbiased study identified two genes, FCGRT And B2Mwhose protein products come together 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 a fetus, but is also present in immune cells and cells that line blood vessel walls – both of which are targets of arteriviruses.

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

Disabling the key component of the FcRn complex – the FCGRT gene – from host cells blocked viral infection, and pretreatment of 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 based on differences in the species-specific FcRn sequence, meaning that in some cases this protein will function as a barrier against cross-species infections.

“Chimpanzees and humans all have virtually the same genes, but the order of those genes is slightly different,” Bailey said. “All mammals have the FcRn receptor, but their ability to support infection with a particular arterivirus may vary.”

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

A series of experiments with different cell types and the use of multiple viral strains in the new study showed that CD163 does play a role in infection by most arteriviruses, but it cannot occur alone – interaction with FcRn is also key to facilitating of arteriviral infection of host cells.

Describing these steps for arterivirus infection is an important milestone, the researchers said.

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

One of those “disruptors” could be blocking the receptor – so showing that an existing monoclonal antibody can stop viral infections in cells is also a plus for scientists studying viruses through a lens of pre-pandemic preparedness.

“If any of these viruses were to emerge in humans, I think we would be in big trouble,” Bailey said. “So that’s the motivator for me.”

This work was supported by grants from the National Institutes of Health, the University of Wisconsin-Madison Startup Funds, 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; Ohio State’s Devra Huey, Makky Mousa-Makky, Jared Compaleo, Fei Jiang and Haichang Li; 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.