Winter 2019

How the Flu Builds a Better Mousetrap

New research reveals how protein molecules seek to hijack target cells.

By Kim Thurler

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Illustration: Stuart Bradford

For the first time, scientists have directly visualized in real-time the structural changes in the surface protein of the influenza virus that may help the virus fuse with—and enter—target cells. Researchers at Tufts University School of Medicine found that single molecules of the protein hemagglutinin (HA) residing on the surface of the virus unfold to stretch toward target cells, then refold and try again, as many as ten times per second. The discovery, published in the journal Cell, shows the flu virus to be more dynamic than previously thought and may lead to more effective vaccines and better understanding of other viruses, such as Ebola, HIV, and SARS.

For decades, influenza has served as the study model for a large class of viruses that enter cells by a common mechanism: An envelope protein on the surface of these viruses must attach the virus to the cell membrane, and then fuse the virus and the cell. Fusion allows release of the virus contents into the cell, so it can take over the cell’s internal functions and replicate. Influenza’s envelope protein, HA, has long been a template for fusion mechanisms in other viruses.

“Envelope proteins have been described as old-fashioned mousetraps, set in a static, spring-loaded state, waiting to be triggered by interaction with a target cell,” said the study’s senior author James Munro, assistant professor of molecular biology and microbiology at the medical school. “Once triggered, they undergo a dramatic change in their three-dimensional structure, enabling fusion and entry into the target. However, despite some hints in previous research, this process hadn’t been directly observed, and it was widely thought that each protein molecule on the surface of the virus had only one chance to spring its trap.”

Using an advanced imaging technology—single-molecule Förster resonance energy transfer, or smFRET, which measures nanoscale distances within single molecules labeled with fluorescent dyes—and then performing significant computational analyses of the data, the Tufts researchers generated the first real-time visualization of the changing shape of individual HA molecules seeking cellular targets. To facilitate the experiments, the HA molecules were imaged while on the surface of an unrelated virus.
What the researchers discovered was a versatile and dynamic mousetrap that was far from the one-and-done model previously assumed. “The fact that this viral molecule can reconfigure itself, then reverse that configuration and rapidly repeat that sequence multiple times changes the way we think about virus entry,” Munro said.

Reversibility may benefit the virus in several ways, including preventing early activation in the absence of an appropriate target, enabling virus molecules to increase efficiency by synchronizing their efforts, and confusing a cell’s protective antibodies, which must recognize the shape of a virus to defend against it.

Research is still needed to prove repeatability and reversibility of these protein dynamics in viruses other than flu, and Munro’s lab has done visualization experiments using inert, noninfectious Ebola particles. Munro has received a National Institutes of Health Director’s New Innovator Award to support use of single-molecule imaging to investigate how viruses such as Ebola enter host cells.

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