More than just a mechanical barrier – epithelial cells actively combat the flu virus

HZI researchers examine the way in which epithelial cells react to the flu virus in the lungs



© HZIInfluenza A virus-infected mouse epithelial cells. The nuclei of all cells are stained blue while infected cells are specifically marked using an influenza A virus nucleoprotein-specific antibody.

Every year, we see new flu epidemics all over the world, which vary greatly in terms of their magnitude. Once it has entered the body, the influenza virus multiplies in the epithelial cells on the surfaces of the airways. Nevertheless, this does not go unnoticed and the body combats it actively. Alveolar type 2 epithelial cells can be found in the lower airways. For the first time, scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the Otto von Guericke University Magdeburg have investigated the role which these play in the immune response in the lungs directly in the tissue of mice infected with flu. In doing so, they observed an unexpectedly strong and varied reaction. The scientists published their results in the professional magazine, "mBio".

Even this winter, many people were given first-hand experience of how the real flu is much more than just a normal cold. Although the current flu season has not fully subsided yet and we are still waiting for the final reports, we know that there was a particularly high number of flu infections with severe outcomes this year. The remarkable thing here is that a lot of young people were affected in relative terms. Alongside additional visits to the doctor and hospital stays, which put a strain on both the patients and the health system, the flu even proved to be fatal in a few cases.

If a virus is transmitted from one person to the next, then it must multiply successfully in its new host in order to cause an infection. With the flu virus, influenza A, this happens in the cells of the human airways and the lungs. Their surface is a thin and permeable barrier between the inside of the body and the environment – we refer to this as the epithelium. In severe cases of the flu, the virus penetrates right into the lower airways and uses the alveolar type 2 epithelial cells available there to multiply.

In the past, the role of the epithelium was reduced to a purely mechanical barrier function. However, studies in recent years have shown that the epithelial cells in the airways and lungs possess a multitude of functions which are key from an immunological point of view. What's more, they create an important link to the specific, adaptive immune system. "The way in which the alveolar type 2 epithelial cells react to the flu virus represents a special case as it is precisely these cells which this virus uses to multiply," states Dr Sabine Stegemann-Koniszewski, a scientist in the immune regulation working group at the HZI and lead author of the study.

However, it is not easy for the virus to multiply as the epithelial cells actively defend themselves against the intruder. "We have seen that, on the one hand, they inhibit the multiplication of the virus and on the other hand, they protect neighbouring cells from penetration," explains Prof Dunja Bruder, head of the working group at the HZI and professor of infections immunology at the university hospital of the Otto von Guericke University Magdeburg. "What's more, they attract additional immune cells to the infection site, activate these and therefore initiate additional steps towards an effective immune response." On top of this, the scientists were able to show that the alveolar type 2 epithelial cells respond to neurotransmitters which are sent out in turn by other immune cells as a reaction to the virus.

Previously, the way these cells react to influenza viruses had only been examined in cell cultures. "That has a cruical disadvantage – you do not see the interaction with other cells in the lungs," Bruder points out. Bruder and her colleagues have now successfully examined the reaction of these very epithelial cells in vivo – in other words, in a living organism – for the first time. To do this, they infected mice with the virus and isolated alveolar type 2 epithelial cells on three consecutive days after the infection. This meant that they were able to observe when the cells reacted to the virus, the strength of this reaction, and what they used for the reaction.

"We observed a surprisingly strong, quick and varied reaction," explains Dr Andreas Jeron, the second author of the study. The cells react to the virus on the very first day after infection by activating different genes which are key for an immune response and by actively communicating with their environment to combat the virus.

On the one hand, these results underline the fact the alveolar type 2 epithelial cells are very much more than a mechanical barrier, even when you are infected with the flu virus. On the other hand, they provide important insights with regard to the immunological contribution that these cells make to combatting viruses, which was underestimated up until now. "The more we understand about how the very early response to the virus in the body actually works, the better we will be able to intervene and therefore help the body to combat a flu virus quickly and effectively," concludes Bruder.



Stegemann-Koniszewski S, Jeron A, Gereke M, Geffers R, Kröger A, Gunzer M, Bruder D. 2016. Alveolar type II epithelial cells contribute to the anti-influenza A virus response in the lung by integrating pathogen- and microenvironment-derived signals. mBio 7(3):e00276-16. doi:10.1128/mBio.00276-16.

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