Our understanding of flu infection has just crossed a decisive step thanks to the invention of an unprecedented microscopic observation tool. Researchers have been able to capture, for the first time in real time and at the molecular scale, the complete sequence by which a flu virus introduces itself into a human cell.
The method used, the result of an international collaboration, combines two microscopic approaches to obtain high-resolution images of living cells. It revealed that the entry of the virus does not result from a simple passive collision. On the contrary, it stages a dynamic and coordinated interaction between the viral particle and the membrane of its target cell, a dialogue that precedes the invasion and conditions its success.
Cells actively contribute to the capture and incorporation of flu viruses. Here, a cell and a virus at the center of the image.
Illustration: Emma Hyde / ETH Zurich The molecular ballet of infection
The study, co-signed by teams from ETH Zurich and Hokkaido University, used an innovative combination of atomic force microscopy and confocal fluorescence microscopy. This method, named ViViD-AFM and described in the proceedings of the National Academy of Sciences of the United States
(PNAS), allows to simultaneously follow the topography of the cell and the position of fluorescence-labeled viruses. Unlike destructive techniques like electron microscopy, it keeps the cell alive, thus capturing the full dynamics of the process.
The obtained images show that the virus does not simply force an entry. It moves laterally along the cell membrane, exploring its surface in a movement that researchers compare to surfing. This navigation is guided by the interaction between hemagglutinin proteins on the virus surface and sialic acid receptors present on the cell. The virion thus seeks a zone rich in these receptors, an optimal anchoring point to initiate the internal process.
What most surprised the researchers is the active response of the cell during this phase. The membrane does not remain inert. At the location where the virus attaches, it forms protrusions and dynamic undulations, as if trying to grasp or contain the intruder. This activity, mediated by the cell's actin cytoskeleton, is usually devoted to essential functions like nutrient absorption, a mechanism that the virus hijacks for its own benefit.
A door open to new therapies
The precision of this new imaging method now allows to dissect each step of viral entry with unprecedented accuracy. Scientists were able to observe the localized recruitment of clathrin, a protein that shapes an endocytosis vesicle to internalize the virus. They also noted that the intensity of membrane movements increased when the virus threatened to detach, suggesting an attempt at active retention by the cell.
This ability to observe infection in real-time opens promising avenues for the screening of therapeutic molecules. It becomes possible to test the efficacy of antiviral drug candidates in cell culture and to visualize in real-time their impact on the entry process. One can thus verify if a compound effectively blocks the attachment of the virus, its membrane "surfing", or the formation of the internalization vesicle.
Finally, the scope of this technology is not limited to the influenza virus responsible for the flu. The authors emphasize that the ViViD-AFM platform can be adapted to study the interaction of other viral pathogens with cells, or even to observe the behavior of vaccine nanoparticles. It thus offers a universal observation window on the nanoscopic events that govern interactions at the cellular interface, a powerful tool for fundamental biology and translational medical research.
Article author: Cédric DEPOND