Every winter, as the air sharpens and scarves return to shoulders, an old visitor also makes a reappearance: the flu. It announces itself with fever, aching limbs, and the familiar drip of a runny nose. But behind these symptoms lies a microscopic drama.
The culprit is the influenza virus, hitching a ride on tiny droplets we breathe in. Once inside, it slips past our defenses and begins its quiet invasion, targeting the very cells that keep us alive.
On the surface of the influenza virus are two molecular "keys": hemagglutinin (HA) and neuraminidase (NA). They are the virus's lockpicks, the tools that let it slip into our cells and spread from one host to another.
The flu virus attacks much like a thief looking for unlocked doors. Its HA and NA proteins grab onto tiny molecules called sialic acids on the surface of cells. Once attached, the virus slides along the surface until the cell reshapes itself and swallows the virus inside. This process is called endocytosis.
But watching how the flu virus sneaks into cells has been difficult because standard microscopes can't capture these fast, tiny steps clearly.
In a breakthrough study, scientists from Switzerland and Japan built a new kind of "super microscope" by blending two powerful imaging tools: atomic force microscopy (AFM) and fluorescence microscopy, creating a new method called virus-view dual confocal and AFM (ViViD-AFM). This hybrid system lets researchers zoom in on living human cells with incredible detail. This offers a new real time insight into how the flu virus operates.
For the first time, researchers could actually see the nanoscale drama of influenza invading a cell. But what surprised them most was the target cell's role in this process. Instead of sitting quietly and letting the virus in, the cell seemed to fight back: stretching, shifting, and even trying to grab hold of the virus as if to control the encounter.
"The infection of our body cells is like a dance between virus and cell," suggested Yohei Yamauchi at ETH Zurich.
With their new system, the team watched how single flu virus particles move across the surface of a cell under different conditions, like when specific viral proteins were blocked, when fewer binding sites were available on the cell, or when different virus types were tested. They also studied how the cell's membrane changes shape before and during the virus's entry.
To see the flu virus clearly, scientists often add fluorescent tags that made the virus glow. But their new tool could even follow viruses without any labels. This method lets researchers see both the shape of the cell and the glowing signals from the virus at the same time, giving a detailed picture of how the virus’s proteins connect and interact with the cell.
The study found that flu viruses need bigger bulges on the cell’s surface to get inside. These bulges are made from actin, a protein that helps shape the cell, and they weren’t stopped by certain inhibitors, meaning the process may be similar to other cell activities. Once the virus attaches to receptor clusters, it sends signals that make the cell wrap it in a clathrin coat and build an actin bulge, pulling the virus inward. The virus is then pinched off into a vesicle and carried deeper into the cell, toward the nucleus.
This new microscopy technique could also help shape future medicines. Researchers can use it to test how well antiviral drugs work directly in living cells and see the results in real time. The team also points out that the same tool could be used to study how other viruses behave, as well as how vaccines interact with cells.
ViViD-AFM could become a kind of "window" into the busy life of cells. It may help researchers watch how different shapes of flu viruses attach and enter, how cells release tiny packages called extracellular vesicles, or even how drug‑carrying nanoparticles slip inside. In short, ViViD‑AFM is like a versatile lens that could reshape our understanding of how cells interact with viruses and medicines, opening the door to major discoveries in biology and drug research.
The findings are published in the journal PNAS.
Source: ETH Zurich
