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Deadly protein combination unveils new drug target for viral infections

New research from Cornell University details how two highly lethal viruses have greater pathogenic potential when combining their proteins.

A research team led by Hector Aguilar-Careno, an associate professor at the Department of Microbiology and Immunology, discovered a potentially similar scenario with a pair of viruses, in a study published in Journal of Virology.

"Co-infections with these two viruses can occur at the same host, but we did not know what would happen if their proteins were combined," Aguilar-Careno said. "We have found that not only can they work together, they can work even better than they do separately."

Members of the Aguilar-Careno research team are experts on how the Nipa and Chandra viruses bind and bind their host cells. The natural host of the viruses is a fruit bat; this link was captured as an illustration, chosen for the magazine's front page, by Aguilar-Careno's husband, Armando Pacheco, a staff member at the Cornell Institute of Biotechnology.

The researchers' focus is on viral fusion proteins (or F proteins) and fastening proteins (G proteins). In previous studies, the team discovered how the two proteins physically interact to enable viral infections: A protein G binds to the cell; G then activates F to flip up and down, causing fusion between the cell and the viral membranes – the first moment of infection.

Aguilar-Careno knew this "dance" between G and C was a key step in virus infection, but was curious to know how the dance could change if the proteins got new partners. Since both Nipah and Chandra viruses can potentially infect fruit bats, a protein partner switch is likely to occur in the wild.

He and his team tested different Nipah-Chandra protein combinations in the laboratory, using genetic approaches in human cells. In some couples, the two were holding each other in a tight tango-like embrace. But one hybrid – Chandra X and Nipah G – behaved like Lindsay Hoopers, allowing the protein C to perform "airs" that enhanced the fusion between the virus and the cell.

"This protein combination had a looser interaction," Aguilar-Careno said. "This relaxation actually corresponded to a greater ability to fusion – and therefore implies a greater" ability to cause disease.

This hybrid protein power has interesting implications.

"I think it's fascinating – the tightness of the interaction is so crucial for these two proteins," Aguilar-Kareno said. "If they are too tight, they cannot coordinate properly to get into the cell. And now that we know this, we can use it to stop fusion of viral cells. "

Aguilar-Careno said this type of therapeutic approach could be used to improve vaccine efficacy or as an alternative to vaccines. His lab is working on approaches to vaccinate animal models, as well as therapeutic approaches informed by this new discovery.

The Aguilar-Kareno lab is also working on related research that could lead to vaccine-free or improved vaccines for the treatment of enveloped viruses, which include infectious diseases such as human immunodeficiency virus (HIV) and influenza. The infected viruses are wrapped in an outer layer made of a piece of plasma membrane of the infected cell, which can protect the virus and help it infect other cells.

"Our work can lead to drugs," said Aguilar-Careno, "who provide inventions, such as the flu vaccine, with wider protection and greater efficacy."


Newspaper reference:

Bradell-Tretway, B.C. B. et al. (2019) Nipah and Hendra virus glycoproteins cause comparable homologous but different heterologous fusion phenotypes. Journal of Virology.

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