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Infectious disease

Tracking individual flu viruses shows the antiviral drug zanamivir in action

Watching single virus particles moving and binding to cell membranes could improve understanding of how flu drugs work

by Jyoti Madhusoodanan, special to C&EN
February 25, 2019

 

Micrograph of influenza virus with glycoproteins on its surface.
Credit: Kateryna Kon/Shutterstock
The influenza virus uses the surface proteins hemagglutinin (orange) to attach to cells and invade and neuraminidase (blue) to detach from cells and seek new hosts.

Blame the flu’s infectivity on these two proteins: hemagglutinin (HA), which enables the virus to stick to cells and enter them, and neuraminidase (NA), which cleaves HA bonds to help viral progeny detach from cells to find and invade new ones. A new combination of analytical techniques now offers a way to count how many interactions a single virus’s surface proteins have with cell surface sugars—and reveals an unexpected effect of zanamivir, a common flu medication. The results offer a route to better understand viral infectivity and could aid in designing new drug molecules (Nano Lett. 2019, DOI: 10.1021/acs.nanolett.8b04969).

Flu strains such as H5N1 or H3N2 are named and characterized for the specific HA and NA variants they carry. Although a single HA bond with a receptor is weak, each virus particle forms many such bonds. To infect a cell, multiple HA molecules must bind with sialic acid–containing receptors on the cell surface. Previous studies have determined the average strength and number of bonds a virus makes by measuring, for example, the overall force required to detach a virus from a cell. But these techniques don’t reveal the strength of each individual bond or how dynamic it might be.

To get a more accurate picture of the bonds formed by a single virus, Stephan Block of the Free University of Berlin and his colleagues turned to a combination of techniques: single-particle tracking, which uses real-time imaging to track fluorescent-labeled viruses, and total internal reflection fluorescence microscopy. They created a lipid bilayer containing cell surface receptors to mimic a cell and poured fluorescent-labeled H3N2 virus particles over this layer. The microscopy tracked when particles bound or detached from the surface, and single-particle tracking monitored random viral movements caused by diffusion. Together, the two assays directly observe how many bonds a virus makes with a given cell at a particular moment in time, Block says.

The combination of methods is a “clever experimental design,” says Ravi Kane, who studies the interactions of nanostructures and biological systems at Georgia Tech and was not involved in the study. The study “breaks a complex situation up into simpler pieces,” he says, so researchers can dissect virus-receptor interactions on a fine scale.

The researchers also analyzed the effects of the antiviral drug zanamivir, which is known to block NA activity and thus prevent budding viruses from escaping one cell to infect others. They found that the drug also increased the rate of attachment of viruses to the membrane, keeping viral particles stuck to the membrane longer. The effect was “surprising to me,” Block says, because NA inhibitors are largely studied for their effects on virus egress, not attachment.

Why this occurs is unclear, though it’s possible the effect may be because once NA is inhibited by the drug, it’s unavailable to cleave HA–sialic acid bonds, Kane suggests.

Such studies could help understand relationships between the infectivity of viruses and how they bind or detach and also reveal how different cell-surface proteins or sugars might alter a virus’s response to drugs. Understanding how HA and NA work in concert within a single viral particle can help scientists figure out the full range of virus-cell interactions. Jacob Martin, a postdoctoral researcher at the Massachusetts Institute of Technology, says that “when fighting a pathogen, it’s interesting to know the range of its capabilities, which could affect how different drugs might prevent infections.”

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