Findings Could Foil Two Potential Bioterror Agents

Two lethal and easily transmitted viruses -- both potential bioterror agents -- may soon be much less dangerous, thanks to research led by scientists at Weill Cornell Medical College in New York City.

Hendra and Nipah viruses are related, newly recognized zoonotic viruses that can spread from their natural reservoir in fruit bats to larger animals -- including pigs, horses and humans.

The mode of transmission isn't clear, but is thought to be relatively easy -- either by close contact with an infected host or by breathing in the microscopic pathogens. Infection often leads to a fatal encephalitis, and there is currently no effective treatment against these illnesses. However, researchers at Weill Cornell say that by tweaking a peptide (protein) related to a third pathogen, parainfluenza virus, they may be able to prevent Hendra and Nipah virus from infecting human cells.

The findings are published in this month's issue of the Journal of Virology.

"The goal has been to have some kind of drug like this that could be stored at key points around the world, ready for mobilization in case of an outbreak," explains study senior researcher Dr. Anne Moscona, professor of pediatrics and professor of microbiology and immunology at Weill Cornell Medical College, and attending pediatrician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Public health officials have sounded alarm bells ever since Nipah virus first emerged in pigs and then humans living in Southeast Asia. More recently, cases of Hendra virus began to show up in horses and their human handlers in Australia.

Experts who drew up the U.S. National Institute of Allergy and Infectious Diseases' Biodefense Research Agenda have included both viruses as potential bioterror agents.

"People could, theoretically, go out into the field and collect Hendra virus from bats, for example," Moscona says. "We've been urgently working on this because right now there's absolutely nothing that can be done to stop this fatal, transmissible illness."

Luckily, prior research at Weill Cornell had laid out some important groundwork. The study's lead author, Dr. Matteo Porotto, has worked for years studying these types of microorganisms, using the parainfluenza virus as his model.

"We were able to develop the strategy that we describe in this paper because our work on parainfluenza had already helped us understand how these viruses fuse with host cells," says Porotto, who is assistant professor of microbiology in the Department of Pediatrics at WeillCornellMedicalCollege.

Based on that work, Porotto and Moscona knew that a receptor-binding molecule on the virus -- simply called "G" -- binds to the surface of the cell, and that the role of G doesn't stop there. "When it binds, it activates a special 'fusion protein,'" Porotto explains. "This fusion molecule has to then undergo some shape changes to turn itself into a six-helix bundle. Once that's done, it helps the virus fuse with, and enter, the cell."

However, the Weill Cornell team discovered that a peptide specific to the parainfluenza virus can inhibit this shape-changing step -- stopping fusion cold.

"Surprisingly, this peptide from the parainfluenza virus turned out to be even more effective at inhibiting Hendra virus fusion than peptides derived from the Hendra virus itself," Moscona says. "It also appears to do much the same thing with the Nipah virus, inhibiting fusion there, too."

The Weill Cornell team has bioengineered the parainfluenza virus peptide even further, enhancing its fusion-inhibiting powers. "In preliminary, unpublished data, we've now shown that it works far better than we had even hoped, and that the new peptides will work against both Hendra and Nipah viruses," Porotto says.

Much of this research is modeled on insights gained from two decades of investigation into another lethal virus, HIV. In fact, T-20, or Fuseon -- one of the earliest effective HIV-suppressing drugs -- acts on a similar principle to block that virus' entry into cells.

"Today, HIV-positive patients typically receive a combination of drugs to keep the virus at bay," Moscona notes. "We envisage that a similar strategy might work someday against Hendra and Nipah, where doctors would use a handful of different drugs to stop infection by targeting various points in the viral life cycle."

This research was supported by a Public Health Service grant from the U.S. National Institutes of Health's NorthEast Center of Excellence for Bio-defense and Emerging Infections Disease Research.

"We really couldn't have developed this anti-bioterror agent so quickly without the Center's help -- they really fast-tracked this research," stresses Moscona. "You find something innovative, and the necessary resources are right there."

The researchers say the right balance of lab-based empirical science, conducted with an eye to clinical applications, was also key.

"Our team was able to apply insights gained in the lab to emerging clinical problems," Porotto says. "It's that combination of basic science and clinical expertise that really fosters these types of important, rapid advances."

Participants in the project included Lynne Doctor, Paolo Carta and Dr. Olga Greengard, members of the laboratory of Drs. Porotto and Moscona at WeillCornellMedicalCollege in New York City; and Dr. Michaela Fornabaio and Glenn E. Kellogg, of VirginiaCommonwealthUniversity in Richmond, Va.

Source: NewYork-Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College