A scientific research team from Switzerland and Japan recently recorded for the first time with high spatial and temporal resolution the entire process of influenza virus moving on the surface of living human cells and entering the cells, providing an unprecedented detailed perspective on revealing the initial stage of viral infection. Research shows that host cells are not passive targets, but actively stretch, push and pull when the virus approaches. The relationship between the virus and the cell is more like a precisely coordinated "dance of invasion."
Influenza infection usually begins when virus-containing droplets enter the human body. The virus attaches to the surface of cells such as respiratory epithelium and completes the invasion. Using cultured human cells as a model, the collaborative team developed a specialized microscopic imaging technology that can continuously observe the ultrastructural dynamics of the cell surface under a magnified field of view, thereby "live broadcasting" the complete process of influenza viruses entering living cells for the first time. The project was led by Yohei Yamauchi, professor of molecular medicine at ETH Zurich. He described virus invasion as "like a dance between the virus and the cell." The cell will actively "reach out" in the direction of the virus and participate in the entire process of its being enveloped and endocytosed.
The study found that although the results show that this process only helps the virus complete the infection, the virus actually hijacks the normal endocytic pathway used by cells to take in essential molecules such as hormones, cholesterol, and iron. The influenza virus first needs to bind to specific molecules on the cell surface, and then "slide" along the cell membrane, moving from one position to another on the membrane surface until it finds an area with a high concentration of surface receptors, which becomes its most effective "invasion entrance." When the receptor recognizes the virus and completes its aggregation, the cell membrane will form a gradually sunken pit. A structural protein called clathrin participates in shaping and supporting it, making the pit deepen and eventually wrap the virus around like a pocket to form a vesicle. Subsequently, this vesicle is pulled into the cell, and its surface coating gradually disintegrates, allowing the virus to be released within the cell, starting the next stage of the replication process.
In the past, researchers have tried to use electron microscopes to capture this key link, but such techniques require fixing and destroying cells, and can only obtain static "snapshots", making it difficult to restore dynamic processes. Although fluorescence microscopy can image in living cells, it is limited by spatial resolution and cannot reveal fine structural details such as cell membrane depressions and protein aggregation. To break through these bottlenecks, the team developed a new method that combines atomic force microscopy (AFM) with confocal fluorescence microscopy, named "Virus Visible Dual-Mode Confocal-Atomic Force Microscopy" (ViViD-AFM). On the one hand, this technology uses atomic force microscopy to describe the surface morphology of cells at the nanometer scale. On the other hand, it uses fluorescent signals to mark the positions of viruses and related proteins to achieve simultaneous tracking of structure and function.
With the help of ViViD-AFM, researchers observed that cells actively "cooperate" with the virus at multiple levels to complete the invasion: for example, they precisely recruit clathrin to the location of the virus and help form membrane vesicles that encapsulate the virus. When the virus is slightly away from the cell surface, the cell membrane will "lift" upward, causing obvious deformation and dynamic movement to re-approach and capture the virus. These movements are more intense when the virus deviates slightly. This shows that the influenza virus borrows the highly regulated substance uptake system of the cell itself to a great extent and "reverses" the mechanism originally used for life-sustaining activities as an infection pathway.
The research team pointed out that this new imaging platform is of great significance for the development of antiviral drugs because it can observe the specific effects of candidate drugs on each step of virus invasion in real time in a living cell system, thereby allowing more targeted screening and optimization of inhibition strategies. In addition, ViViD-AFM is not limited to influenza viruses. In the future, it can also be used to study the interaction between other viruses and even vaccine particles and cells. It is expected to provide more comprehensive physical and biological clues in the early stages of infection and provide an experimental basis for the design of new antiviral therapies and prevention methods.