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Deadly protein partnership reveals new drug targets for viral diseases

It sounds like a plot point from a sci-fi movie: two different and dangerous monsters meet, conjoining into a hybrid that is more powerful and deadly than either counterpart. Yet Dr. Hector Aguilar-Carreno, associate professor in the Department of Microbiology and Immunology, and his research team, have proved truth to be stranger than fiction in a recent study published in the Journal of Virology and featured on its cover which details how two highly lethal viruses, Nipah and Hendra, have greater pathogenic potential when their cell-sabotaging proteins are combined.  “Coinfections with these two viruses can occur in the same host, but we didn’t know what would happen if their proteins combined,” says Aguilar-Carreno. “We discovered that not only could they work together, they can work even better than on the original viruses.”

The Aguilar-Carreno research team are world experts on how Nipah and Hendra viruses attach to and fuse with their hosts cells. Their focus is on the viral fusion proteins (or F proteins) and attachment proteins (or G proteins). In previous studies, the team unveiled how the two proteins physically interact to enable viral infections: a G protein attaches, key-in-lock, to the cell. Once attached, G triggers F to perform “gymnastics” – flipping up and back down to trigger fusion between the cellular and viral membranes in the first real moment of infection.

Dr. Hector Aguilar-Carreno

Aguilar-Carreno knew this physical dance between G and F was a crucial piece to viral infection, but was curious to know how that dance might change if the proteins got new partners. After all, both Nipah and Hendra viruses can potentially co-infect their natural host, the fruit bat, meaning that a protein partner-switch is likely to occur in the wild. The interplay between bats and viruses came to life on the issue cover of the Journal of Virology that featured this research, painted by Aguilar-Carreno’s husband, Armando Pacheco.

He and his team tested out different Nipah-Hendra protein combinations using genetic approaches in human cells in petri dishes. In some pairings, the two gripped each other in a tight, tango-like embrace. But one hybrid – a Hendra F and Nipah G – behaved like Lindy Hoppers, allowing the F protein to perform “aerials” that heightened fusion between the virus and the cell. “This combination of proteins had a looser interaction,” says Aguilar-Carreno. “This looseness actually corresponded to greater fusion capability — and therefore greater pathogenicity.”

This hybrid protein power-couple has interesting implications. “I find it fascinating. The tightness of the interaction is so crucial for these two proteins,” says Aguilar-Carreno. “If they’re too tight, they can’t coordinate correctly to get into the cell. And now that we know this, we can leverage that to stop viral-cell fusion,” says Aguilar-Carreno.  He notes that this kind of therapeutic might be used to improve vaccine efficacy, or as an alternative to vaccines. His lab is working on both vaccine approaches on animal models, as well as therapeutic approaches, both helped by this new knowledge.

Aguilar-Carreno’s lab is also working on related research that may lead to vaccine-free therapies or improved vaccines to treat enveloped viruses, which include major infectious diseases such as HIV and influenza. “Our work could lead to drugs that enable inventions such as a flu vaccine with broader protection and greater efficacy,” says Aguilar-Carreno. “The data is looking so good so far that it almost looks made up. We’re very excited about this, and hope to tell the story about these promising advances in the near future.”

-By Lauren Cahoon Roberts

A version of this story appeared in the Cornell Chronicle