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La plataforma permanente Atomium Culture reúne a las universidades, periódicos y empresas más prestigiosos de Europa para promover el flujo del conocimiento más allá de fronteras, entre sectores y hacia el público en general.

How Strong Is a Virus? Measuring Single Virus Cell Attachment Forces Motivates the Design of New Antiviral Drugs

Por: | 26 de agosto de 2013

JZ B127 - Sieben - Figure
By Christian Sieben, Humboldt-Universität zu Berlin

Flu epidemics remain a constant threat for humans, even though recent `bird and swine flu´ cases have brought this threat back into public awareness. The causative pathogen, the influenza virus, has been under extensive research since decades, but its infection mechanism is still not fully understood.

In the group of Andreas Herrmann, professor of Molecular Biophysics at the Humboldt-University in Berlin, we aim to understand the initial steps of the influenza virus infection. Due to a lack of specialized proteins, viruses by themselves are not able to reproduce. To compensate for this limitation, they highjack the protein machinery of their host cell. To this end, the virus features proteins on its surface to find and attach to a suitable host cell. The most abundant of these so-called spike proteins, hemagglutinin (HA), mediates the initial viral attachment to the surface of the cell. This protein is already of high medical relevance since HAs of the relevant influenza strains are used as part of a vaccine to immunize people against the yearly influenza. But, what if you are already infected?

Current therapies target viral proteins that are necessary during later steps of the influenza replication cycle, however, there is a strong tendency of viruses to develop resistances against these therapies. Thus, we want to find a different strategy: prevent the virus attachment to the host cell surface in the first place. To understand this initial step of influenza virus infection, we measure the force that is required to attach a single virus particle to a host cell. But, how is it possible to measure such tiny forces?

Together with biophysicists from the University of Linz, we put single viruses on a microscopic leash. The leashing molecule is attached to a very sharp tip that is used as a surface sensor. This technique is called atomic force microscopy (AFM) and works, in principle, like a record player. The record or disc is the sample and the cantilever carries the tip to probe the surface of the sample. Rather than making music, the cantilever is used as a fishing pole to lower the leashed virus into a pool of cells. Once a virus is bound, it is immediately pulled back and lowered again. Each time a virus is detached from the surface of a cell, the necessary force is detected. By using this technique, we are able to measure the forces between individual HA proteins and the cell surface receptors. We found that the force is only about 10 piconewton. To get an idea of this number, imagine all people of the world lifting a single 1 Euro coin—each person would have to invest a force of 10 piconewton. In addition, in comparison with other forces in viral or bacterial systems, this force is extremely small and thus has an important consequence: the virus must form multiple bonds in order to bind itself stably to a host cell.

This multiple bond mechanism is called multivalency and is observed in other parts of nature. For instance, a gecko walking on a flat glass surface keeps himself of the ground by using multiple hair-like structures on his feet. Each of these hairs also forms a very weak interaction, but all together they enable the gecko to climb on almost every material. The multivalent effect has another advantage: due to the weakness of every single bond, it is easier to lose and re-form them individually. Of course, the gecko wants to move, so must the virus -- once attached, it has to stay in motion in order to find a suitable region to enter the cell.

We now use this attachment mechanism to develop new antiviral drugs that inhibit the binding of the virus to the host cell. Within a German Research Foundation (SFB 765) funded collaboration with chemists from the Free University in Berlin, we designed multivalent particles, inspired from the viral structure itself. These nanoparticles are spherical and present multiple copies of the HA cellular receptor. Using such particles to inhibit an influenza virus sample, we discovered that the size of the particle and the number of receptors play an important role and can dramatically change their efficiency. An optimal effect was achieved by selecting a diameter that actually matched the size of the virus, with the receptor density about 10 times higher than the number of HAs on the virus. In this configuration, the nanoparticles mimic the cell surface and can efficiently capture viruses before they can bind to the host cell surface.

This work shows that by learning from nature, inhibitors can be developed that mimic the cell surface, which can efficiently bind influenza viruses to suppress their infection.


Christian Sieben
Humboldt-Universität zu Berlin

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