Aarhus University Seal

On the trail of brand new layers in our immune system

There is accumulating evidence to suggest that the immune system of the human brain has an as yet overlooked layer – and that this layer plays a crucial role during viral infections in the brain. Two scientific articles from researchers at Aarhus University support this new understanding of the brain's defence against infections.

Brain cells, the neurons, are vulnerable. If a neuron dies, it is gone, and infections in the brain are therefore always serious. They can lead to inflammation, which often kills brain cells. However, new biomedical research from Aarhus University suggests that the cells of the brain have a weapon –autophagy - against infections at their disposal, which has thus far not been described.. Autophagy is a process that takes place inside cells, where damaged parts of the cell or an intruder, such as a virus, are encapsulated and rendered harmless – and furthermore, this is done without harming the cell or initiating of inflammation.

This new knowledge about autophagy and potentially other similar processes is ground-breaking and may constitute a completely new layer in the human immune system. Such new insight has potentially crucial significance for future treatment of e.g. meningitis and encephalitis (inflammation of the brain) caused by herpesvirus.

Two complementary articles

Two professors from the Department of Biomedicine at Aarhus University are behind the new knowledge: Trine Hyrup Mogensen and Søren Riis Paludan in an international collaboration. Their research is presented in scientific articles in two different journals: a review article in Nature Reviews Immunology and a research article in Science Immunology. The review article was published in August, while the research article is published today on 11 December. According to Søren Riis Paludan, the two articles complement each other very well:

"In the review article, we’ve summarised a large part of the past five to ten years of knowledge about the immune system, and here we suggest that our immune system has a non-inflammatory layer, which protects us from activating inflammatory reactions throughout the body every time we are infected by  virus or bacteria. In the second article, the research article, we describe a specific example of such an immune-mechanism, and we thus demonstrate that it’s not pure speculation, but that the phenomenon actually exists," says Søren Riis Paludan, who envisages the new knowledge possibly leading to a completely new branch of immunology research over time. 

Data from 15 patients with rare disorders

The research article is based on data from 15 Danish patients with a rare form of meningitis, Mollaret’s meningitis. The meningitis is triggered by herpesvirus, and the disease is characterised by recurrence again and again due to repeated reactivation of the virus. The genes of the patients have been mapped out, and the genes from two patients are described in extra detail, because genetic defects render their brain cells unable to perform autophagy and thus eliminate the infection.

"We demonstrate that when cells from these patients are infected with herpes simplex virus, the virus reproduces intensely in the cells, and this leads to cell death. But conversely, if we insert the defective autophagy-related gene in the cells, they become able to fight the viral infection and survive. This strengthens our theory about the importance of autophagy – that it plays a surprisingly important role for the immune system," says Trine Hyrup Mogensen. The phenomenon of autophagy is well-documented, but its significance in the fight against viruses has thus far been overlooked. In particular, it is new knowledge that defects in autophagy are linked to infectious diseases in humans and can thus constitute a new class or category of primary (congenital) immune defects.

"This is probably a general principle for the immune response against  viral infections, and it can be thought to play a particularly important role in the brain, where excessive inflammation has such profound negative consequences," says Trine Hyrup Mogensen. Thus, the discovery can have major perspectives for the future treatment of viral infections, including everything from influenza to Covid-19, because there are  drugs that stimulate the autophagy processes, and it may be possible to prevent not only the rare form of meningitis, but also to treat other infections in the brain.

As Trine Hyrup Mogensen puts it: "In unfortunate circumstances, numerous  viruses can cause infections in the brain, and it is important that the brain can eliminate viruses without at the same time creating excessive inflammation that leads to tissue damage and serious symptoms in the patients." 

About the studies

One of the articles is a review article, while the other is basic research with international participation. Part of the research has been carried out at Aarhus University Hospital.

Partners: Imperial College London, Rigshospitalet and Hillerød Hospital.

External funding: The Danish Council for Independent Research – Medical Sciences; the Lundbeck Foundation; the Novo Nordisk Foundation together with Horizon 2020 Maria Schlodowska Curia Training Network; and the Aarhus University Research Foundation.

Link to the article in Nature Reviews Immunology: https://www.nature.com/articles/s41577-020-0391-5

Link to the article in Science Immunolgy: 

http://immunology.sciencemag.org/lookup/doi/10.1126/sciimmunol.abc2691

Contact

Trine Hyrup Mogensen is professor at the Department of Biomedicine and a medical specialist at the Department of Infectious Diseases, Aarhus University Hospital, as well as being affiliated with the Department of Clinical Medicine under Aarhus University.

Her research areas are infection immunology and primary immune defects.

Mail: trine.mogensen@biomed.au.dk

Mobile: (+45) 2012 5280

Søren Riis Paludan is professor at the Department of Biomedicine. His primary research area is the immune system, in particular the immune systems and viruses.

Mail: srp@biomed.au.dk

Mobile: (+45) 2899 2066