Viruses under the super microscope: How influenza viruses communicate with cells

Viruses have no metabolism of their own and must therefore infect host cells in order to replicate. Contact between the virus and the cell surface is a crucial first step, which can also prevent infections if entry into the cells is blocked. “The interaction with a host cell is dynamic and transient for influenza viruses. In addition, associated processes occur at the nanoscale, requiring super-resolution microscopes for a more precise investigation. Using conventional approaches, it has therefore not been possible to investigate this important first contact in more detail,” says Prof. Christian Sieben, head of the junior research group “Nano Infection Biology” at HZI, explaining the challenge the team has faced.

In collaboration with Prof. Mark Brönstrup’s department “Chemical Biology” at HZI, his team has developed a universal protocol to investigate how viruses communicate with host cells. To do this, the scientists immobilized viruses individually on microscopy glass surfaces. Cells were then seeded on top. In conventional experiments, the viruses are added on top of pre-seeded cells. “The advantage of our ‘upside-down’ experimental setup is that the viruses interact with cells but do not enter them — the critical moment of initial cell contact is thus stabilized and can be analyzed,” says Sieben.

Using the example of a seasonal influenza A virus, the researchers used high-resolution and super-resolution microscopy to show that contact between the virus and the cell surface triggers a cascade of cellular reactions. First, the cellular receptors accumulate locally at the virus binding site. This is due to the fact that the receptors move more slowly through the cell membrane near the binding site and are therefore more abundant locally. Subsequently, specific cellular proteins are recruited and finally the actin cytoskeleton is dynamically reorganized.

However, the researchers applied their method not only to an established influenza A model, but also to a novel influenza strain of animal origin: the H18N11 virus, which is found in bats in Central and South America. Unlike most influenza viruses, which bind to glycans — i.e. carbohydrate chains on the cell surface — for infection, the H18N11 virus has a different target. “This virus binds to MHC class II complexes — protein receptors that are typically found on certain immune cells,” says Dr. Peter Reuther, research group leader from the Institute of Virology of the Medical Center — University of Freiburg. He is studying the cell entry of bat-derived H18 influenza A viruses.

Using single-molecule tracking, the researchers were able to show for the first time that MHCII molecules cluster specifically on the cell surface upon contact with the virus — a process that is essential for the virus to enter the cell. The teams from Braunschweig and Freiburg have thus characterized a new model of influenza A infection: the binding to MHCII as an alternative receptor and the associated dynamic reorganization of the cell surface. “The finding that influenza viruses do not bind exclusively to cellular glycans opens up new perspectives for research into these pathogens,” says Reuther. “Particularly in view of their zoonotic potential, it is crucial to better understand these alternative receptors.”

The virus-cell binding step is also the focus of the EU project COMBINE, which was launched at the beginning of 2025 and is coordinated by HZI researcher Sieben. In COMBINE, scientists from five European countries are investigating the virus entry process of newly emerging viruses, especially those with pandemic potential. “This process is a potential target for antiviral therapies. The methodology we have developed to investigate the virus entry process can be applied to many other viruses,” says Sieben. The new results not only provide detailed insights into the biology of influenza viruses. They also provide a methodological basis for investigating the entry mechanisms of potential pandemic pathogens in a more targeted manner — and thus identifying new targets for antiviral therapies.