For the first time in virology, Fabris and her team will use imaging tools with gold nanoparticles to monitor mutations in the influenza virus, with unprecedented sensitivity, when it enters cells. Fabris will soon receive a $820,000 grant from the Defense Advanced Research Projects Agency (DARPA). It’s part of a four-year, $5.2 million INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program.
Fabris’s work is beginning as New Jersey weathers a high rate of influenza activity this year.
“Before we can understand how to make these therapeutic particles, we need to understand how viral mutation works,” said Fabris, an associate professor in the Department of Materials Science and Engineering.
DARPA says it wants to harness TIPs – tiny virus-like entities with engineered genetic material that encodes defective viral proteins. TIPs, like viruses, can enter cells, but they don’t replicate unless the cells are also infected with the virus. RNA viruses like influenza are coated by a protein-studded membrane envelope, Fabris noted.
In a cell infected with both a flu virus and a TIP, the cell makes copies of the TIP genome that compete for viral proteins. The goal is for harmless TIPs to outnumber flu virus genetic elements so infected cells would generate relatively few infectious viruses and a bumper crop of “dud viruses” with TIP genes, rapidly diluting the harmful viruses and halting the infection, according to DARPA.
In preliminary studies funded by DARPA, TIPs in cells grown in culture dishes slashed viral counts by nearly 20-fold. But the INTERCEPT program, seeking enhanced anti-viral performance, will support testing of TIP safety and effectiveness in animal models, DARPA says. It also seeks to determine whether TIPs, through spontaneous mutations, can keep up with new tricks that viruses may develop while evolving.
The INTERCEPT program features a multidisciplinary team of virologists, evolutionary biologists, mathematicians and materials scientists from North Carolina State University (Ruian Ke), Duke University (Katia Koelle), University of Illinois at Urbana-Champaign (Christopher Brooke), Montana State University (Connie Chang), and Rutgers. The focus is on discovering how the influenza virus mutates at the cellular, animal and population levels, said Fabris, who works in the School of Engineering. One goal is to predict whether TIPs will keep up with flu virus mutations.
“Ideally, the TIPs will be introduced into influenza virus populations and compete for protein, so the virus will starve and not be able to reproduce,” she said.
Her role will be to provide imaging and quantification methods to study, in cells and eventually animals, which parts of the influenza virus genome have mutated and to what degree. It will be the first time that surface enhanced Raman scattering, which measures vibrations in molecules and therefore reports on their chemical composition and structure, will be used in virology, she said.
Each molecule has a unique vibration frequency, and complex molecules have complex vibration patterns, said Fabris, who began using the technique 11 years ago.
She and her team will use gold nanoparticles to examine and quantify the nanoparticles inside cells. She uses gold nanoparticles because they localize the light similarly to a lens and enhance the observed signal intensity.
“Our research will have repercussions, for example, in how to do sequencing of genes in a way that is cheaper and deeper compared with traditional sequencing,” Fabris said.