NIAID Awards Shurer $1.5M to Solve Viral Paradox

Many symptoms of Influenza A—one of the viruses responsible for seasonal flu outbreaks—feel counterintuitive. You run a high fever but feel so cold you may shiver. Your nose is alternately stuffed and runny.

Even the way flu viruses get into our cells seems paradoxical.

“Flu has two major proteins on its surface, and those two proteins have apparently contradictory functions,” said Carolyn Shurer, an assistant professor in the Department of Chemical and Biomolecular Engineering. “It jumps right out of the very first few paragraphs of almost all Influenza A papers.”

To make us sick, pathogens like Flu A have to get through a protective boundary around our cells called the glycocalyx. This layer anchors to the cell membrane and bristles with sugars, mucins (mucus-forming proteins), and other proteins like a fuzzy sweater bristling with hairs.

Scientists have known for decades that Flu A has two major surface proteins, hemagglutinin (HA) and neuraminidase (NA). HA binds to sugars, which makes sense for a virus wanting to burrow towards a host’s cell membrane. But NA’s only function is to cut sugars.

“People have mostly thought of the role of NA as releasing (new) viruses off the cell once you’re already infected, but that doesn’t explain the contradictory role on the infection side of that process,” Shurer said. “If we knew the very, very early molecular steps for how viruses actually enter our cells, then we could deploy targeted antivirals to prevent that initial stage of infection before the virus can even get a chance to replicate.”

Shurer researches the fundamental physics of how proteins and sugars are arranged within living cells, and how that arrangement affects cellular functions. Years of observing how different surface molecules change the structure of cell membranes led her to propose a stunning new hypothesis: NA’s role is to trick a cell into welcoming the flu inside.

This fall, Shurer received an extremely competitive, $1.5 million National Institute of Allergy and Infectious Diseases (NIAID) New Innovators Award to investigate her potentially groundbreaking theory.

As part of the National Institutes of Health (NIH), NIAID is committed to advancing foundational research on host-microbe interactions and developing novel prevention strategies against infectious diseases. The New Innovators Awards support early-career researchers proposing creative, potentially impactful research that is too high-risk for other funding mechanisms.

“Infectious disease research is one of the harder topic areas to be competitive in, but the NIH NIAID is very aware that not every single proposal will result in a commercialized product,” said Shurer. “I think one of the great things about funding fundamental research is that it really does lead to understandings and breakthroughs in unexpected ways.”

Tricking the Glycocalyx

The glycocalyx is the body’s first line of defense against invaders, protecting the cells along the respiratory tract, digestive tract, and every gland and duct in our bodies.

But the glycocalyx can’t exclude everything. Nutrients and signaling molecules have to get in to make sure the cells stay healthy and function together properly. Specialized signals on the surface of such packages let a cell know that it’s time to bud inward, engulfing the contents in a process called endocytosis.

One of the signals to begin endocytosis is when specialized molecules in the glycocalyx, such as the protein galectin, bind surface sugars together in a process known as cross-linking.

“This mechanism of endocytosis through cross-linking of the glycocalyx (sugars) is moderately well established, but no one has (considered) viral entry as going through that pathway,” Shurer explained. “The innovation of (my) proposal is the idea that NA may have a role in reorganizing the glycocalyx to increase (viral) infiltration (into a cell).”

Shurer believes that the NA might trim sugars in a way that exposes new binding sites for galectins, encouraging cross-linking—and telling the cell that something tasty or important has arrived.

Earlier Interventions

Shurer and her team at the University of Tennessee will investigate Influenza A’s mechanism of infection in detail over the next five years. If their results support Shurer’s hypothesis, we could enter a new era of prophylactic (preventative) treatment strategies for viral illnesses.

“If this is a major pathway that’s causing viruses to enter our cells, it gives us a whole new category of molecules that we can target to prevent viral entry,” Shurer explained.

She envisions antiviral drugs targeting this entry pathway being used by front-line and humanitarian workers in pandemic or endemic situations, especially before a vaccine has been developed. The prophylactics could also be used to protect elderly people, young children, or people who are unable to get vaccinated for medical reasons.

In fact, the possibilities aren’t limited to viruses like the flu.

“A lot of pathogens actually interact primarily with our bodies through our glycocalyx,” Shurer said, “so in the event that the research reflects that our hypotheses are true, there’s opportunity for (applications in a) wide range of infectious diseases.”

Contact

Izzie Gall ([email protected])