Potential New Drug Targets ID'ed for Deadly Viruses

New research from investigators at Cornell University not only uncovered how two highly lethal viruses have greater pathogenic potential when their proteins are combined but may have also stumbled upon potential novel targets to combat these diseases. The Cornell team was studying how the Nipah and Hendra viruses attach to, and fuse with, their hosts’ cell within the fruit bat. Findings from the new study were published recently in the Journal of Virology “Nipah and Hendra Virus Glycoproteins Induce Comparable Homologous but Distinct Heterologous Fusion Phenotypes.”

“Co-infections with these two viruses can occur in the same host, but we didn’t know what would happen if their proteins combined,” noted senior study investigator Hector Aguilar-Carreno, PhD, associate professor in the department of microbiology and immunology at Cornell. “We discovered that not only could they work together, but they can also work even better than they do separately.”

The researchers’ focus is on the viral fusion proteins (or F proteins) and attachment proteins (G proteins). In previous studies, the team unveiled how the two proteins physically interact to enable viral infections: A G protein attaches to the cell; G then triggers F to flip up and down, triggering fusion between the cellular and viral membranes—the first moment of infection.

“We compared the fusogenic capacities between homologous and heterologous pairs of NiV and HeV glycoproteins,” the authors wrote. “Importantly, to accurately measure their fusogenic capacities, as these depend on glycoprotein cell surface expression (CSE) levels, we inserted identical extracellular tags to both fusion (FLAG tags) or both attachment (hemagglutinin [HA] tags) glycoproteins. Importantly, these tags were placed in extracellular sites where they did not affect glycoprotein expression or function. NiV and HeV glycoproteins induced comparable levels of homologous HEK293T cell-cell fusion.”

Interestingly, the scientists knew this “dance” between G and F was a crucial step in viral infection but was curious to know how the dance might change if the proteins got new partners. Since both Nipah and Hendra viruses can potentially co-infect fruit bats, a protein partner switch is likely to occur in the wild.

The team tested out different Nipah-Hendra protein combinations in the lab, using genetic approaches in human cells. 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,” Aguilar-Carreno explained. “This looseness actually corresponded to greater fusion capability—and therefore an implied greater” ability to cause disease. I find it fascinating—the tightness of the interaction is so crucial for these two proteins. 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.”

The Cornell team also working on related research that may lead to vaccine-free therapies or improved vaccines to treat enveloped viruses, which include infectious diseases such as human immunodeficiency virus (HIV) and influenza. Enveloped viruses are wrapped in an outer coat made from a piece of the infected cell’s plasma membrane, which may protect the virus and help it infect other cells.

“Our work could lead to drugs,” Aguilar-Carreno concluded, “that enable inventions such as a flu vaccine with broader protection and greater efficacy.”