Key protein helps viruses invade mammalian cells

Scientists studying animal viruses that have the potential to infect humans have identified a critical protein that could enable the spread of a family of organisms called arteriviruses.

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

Arteriviruses are common in many species of mammals around the world that serve as natural hosts – such as non-human primates, pigs and horses – but have not previously been detected in humans.

The researchers' goal is to better understand the mechanisms of an arterivirus infection in order to estimate what the risk of infection is to humans and what preparations might be necessary if a spillover occurs in the future.

“It's important to remember that we are essentially immunologically naïve in that we have no known arteriviruses that infect people, so we cannot rely on pre-existing immunity to help us,” said co-lead 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 Nature communication.

Many natural hosts of arteriviruses show no signs of disease, but the virus that infects pigs can cause pneumonia and abortions in pregnant pigs, 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 as they find new hosts – giving them time to evolve and increase their chances of transmission.

The research team set out to find proteins in mammals that arteriviruses use as receptors to enter host cells and make copies of themselves. Bailey used genome-wide CRISPR knockout screening technology to identify specific genes that, when disrupted, make cells resistant to viral infections. Such genes would then be considered essential to the viral infection process. The unbiased screening 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 special role in transporting antibodies across the placenta to the fetus, but is also found in immune cells and cells lining the walls of blood vessels – both targets of arteriviruses.

The results of this study showed that FcRn is used for host cell entry by at least five arteriviruses that infect monkeys, pigs, and horses, respectively: three different strains of simian arteriviruses, Porcine Reproductive and Respiratory Syndrome Virus 2 (PRRSV-2 ) and equine arteritis virus (EAV).

Switching off the main component of the FcRn complex – des FCGRT Gene – from host cells that blocked viral infection and pretreatment of cells with a monoclonal antibody against FcRn that were protected from infection.

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

“Chimpanzees and humans have virtually all the same genes, but the sequence 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 screening also identified a gene encoding another surface protein, CD163, which Warren and colleagues had previously found to be a gatekeeper to an arterivirus called Simian Hemorrhagic Fever Virus (SHFV) infecting a cell.

A series of experiments in different cell types and using multiple virus strains in the new study showed that while CD163 plays a role in infection by most arteriviruses, it cannot act alone – interaction with FcRn is also key to facilitating arteriviral Infection of host cells.

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

“When we look at the biology of viruses, 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 these “disruptors” could be blocking the receptor – so demonstrating that an existing monoclonal antibody can stop a viral infection in cells is also a plus for scientists studying viruses from a prepandemic preparedness perspective.

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

Reference: Shaw TM, Huey D, Mousa-Makky M, et al. The neonatal Fc receptor (FcRn) is a pan-arterivirus receptor. Nat Commun. 2024;15(1):6726. doi: 10.1038/s41467-024-51142-x

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