Cells actively help to capture and incorporate influenza viruses. Here, a cell is shown, with a virus in the center of the image. Credit: Emma Hyde / ETH Zurich
Scientists have captured an unprecedented, real-time view of influenza viruses as they move across and slip inside human cells.
The footage reveals that cells are far from passive targets and instead push and pull against the virus in a surprisingly active struggle.
Viewing Influenza Infection With New Precision
Fever, sore muscles, and a runny nose often signal the arrival of winter, and with it, the yearly rise in flu cases. Influenza infections begin when virus-filled droplets enter the body, and the viruses latch onto and infect human cells.
A collaborative team from Switzerland and Japan has examined the influenza virus at an extremely detailed level. They developed a specialized microscopy method that lets them zoom in on the outer surface of human cells grown in a Petri dish. With this approach, they were able to watch, for the first time, how influenza viruses move into a living cell while capturing the process in high resolution.
Under the leadership of Yohei Yamauchi, Professor of Molecular Medicine at ETH Zurich, the researchers noticed something unexpected. Human cells do not just sit idle while the virus approaches. Instead, they appear to reach toward it. “The infection of our body cells is like a dance between virus and cell,” says Yamauchi.
How Influenza Viruses Move Across the Cell Surface
Even though cells gain nothing from helping a virus, the interaction appears active because influenza takes advantage of a routine cellular uptake pathway. This pathway is normally used to transport essential molecules, including hormones, cholesterol and iron, into the cell.
Influenza viruses must attach to certain molecules on the cell surface to begin this process. Their movement resembles surfing along the membrane, with the virus gliding from spot to spot until it finds an area packed with surface receptors. A location with many receptors close together provides the most efficient point for entering the cell.
When the cell’s receptors detect a virus at the membrane, they trigger the formation of a small indentation. A structural protein called clathrin shapes and supports this growing pocket. As the indentation deepens, it wraps around the virus and forms a vesicle. The vesicle is then drawn inside the cell, where its coating dissolves and releases the virus.
For the first time, researchers have observed live and in high resolution how influenza viruses infect living cells. This was possible thanks to a new microscopy technique, which could now help to develop antiviral therapies in a more targeted manner.
Earlier Imaging Methods Could Only Capture Snapshots
Previous attempts to study this key moment in infection relied on approaches such as electron microscopy, which requires destroying the cells, limiting researchers to single still images. Fluorescence microscopy is another option, but it provides only low spatial resolution and cannot capture fine structural details.
ViViD-AFM Offers a Real-Time View of Viral Entry
The newly developed method combines atomic force microscopy (AFM) with fluorescence microscopy. Known as virus-view dual confocal and AFM (ViViD-AFM), it enables scientists to monitor the intricate steps of viral entry as they take place.
With ViViD-AFM, the researchers showed that cells actively assist the virus on multiple levels. They draw in clathrin proteins to the exact site where the virus is positioned. The membrane also lifts upward toward the virus, creating movements that intensify if the virus drifts slightly away from the cell surface.
A Valuable Tool for Antiviral Development
This technique offers important advantages for antiviral drug research because it allows scientists to test how potential treatments behave in real time within cell cultures. The study team also notes that ViViD-AFM may help reveal how other viruses or even vaccines interact with cells, giving researchers a powerful way to study infection from its earliest moments.
Reference: “Enhanced visualization of influenza A virus entry into living cells using virus-view atomic force microscopy” by Aiko Yoshida, Yoshitsugu Uekusa, Takeshi Suzuki, Michael Bauer, Nobuaki Sakai and Yohei Yamauchi, 18 September 2025, Proceedings of the National Academy of Sciences.
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