Our brains are very sensitive to infections, and a research group from Aarhus University has found a new mechanism which reduces damage to the brain following infections. Viral infections in the brain activate its immune system, and this is necessary to fight the infections – but at the same time, the immune system is often the cause of irreparable damage in the brain.

2020.10.28 | Ib Salomon

The brain has its own immune system. It contains immune cells which are not found anywhere else in the body, and these play a crucial role when the brain is affected by viral infections such as e.g. herpes simplex. Unfortunately, the immune system sometimes overreacts, and this can lead to damage in the brain. In such cases the immune system needs to be shut down. Clarifying how to “put out these fires” is the focus of a team of researchers from Aarhus University under the leadership of Associate Professor Line S. Reinert. They have now come so far that their findings have recently been published in the Journal of Clinical Investigation.

The new knowledge may have significance for the understanding and treatment of a number of diseases in the brain where it is known that the immune system is over-activated.

 

How the brain reacts to an infection

In the past, it was believed that the brain was so well protected by the blood-brain barrier that it did not need any immune system, and even now our knowledge of the disease mechanisms in the brain remains sparse because the brain is so inaccessible. While it is possible to examine spinal fluid, it is, for example, not easy to take tissue samples of the brain, so the researchers have taken a different route: They have studied brains from mice and brain tissue from people who have died due to infections in the brain. To do this they received help from colleagues in the Netherlands, where five patients died of a herpes simplex infection in the brain. In addition, Line Reinert and her research colleagues have cultivated specific types of brain cells in the laboratories at the Department of Biomedicine. 

In this way, the research team has made a great deal of progress in clarifying and understanding how the brain reacts to an infection:

  "We now know how the herpes simplex virus migrates into the brain through the ganglia, that’s to say the nerve cells. Inside the brain cells, the virus multiplies itself and is then able to spread from nerve cell to nerve cell. In mice, the virus ends up in the brain stem, but in humans the frontal part of the brain is also attacked," explains Line Reinert. For example, this turned out to be the case in the patients in Holland. A study of their brains showed that in some areas there were particularly large amounts of virus, and that there were a great deal of dead brain cells in these areas.

"When there is a viral infection, the brain cells sound the alarm by producing interferon, which is a protein with a range of functions. Among other things, this hinders the virus from multiplying, and it regulates other proteins upwards, so that the immune system is strengthened."

A cell type, called microglia, acts metaphorically as the brain's fireman in an attempt to quell the infection. But it turns out that just as a firefighter can do more harm than good by spraying far too much water on a fire and thereby destroying the house, so too can the brain's alarm system also overreact and start destroying the brain tissue.

A delicate balance if cell death is to be avoided

"So how do we shut down an immune system that is overreacting? This is what we’ve examined, and among our discoveries is the fact that infections in the brain trigger cell death. This may occur in many different ways, some of which are innocuous, while others are harmful. The innocuous way to get rid of the immune cells that overreact is for the brain to begin a programmed cell death called apoptosis. This leads to the nerve cells almost wrinkling together like a raisin," says Line Reinert.

During their study, the researchers have worked with the brains and brain cells from two strains of mice. In one of the strains, the brain reacted to infections by triggering cell death or apoptosis, while apoptosis did not occur in the other strain. By using these two strains of mice, the researchers have clarified that two proteins called cGAS and STING play an important role in managing the delicate balance between activating the immune system and, at the same time, avoiding cell death if the immune system is overactive. This has emphasised that the brain's self-regulation of apoptosis plays a key role in limiting damage in the brain. The researchers have noted that there is at present intense interest in the development of substances that can activate and inhibit STING and be used clinically. "Therefore, fully understanding the underlying biology is absolutely crucial," emphasises Line Reinert.

The self-regulation of the brain is the focal point of the researchers’ work, and the next step is to study whether the new findings can be utilised, for example by investigating whether the same mechanisms are in play in other diseases of the brain in which the immune system is over-activated. This includes disseminated sclerosis, Alzheimer's disease and Parkinson's disease.

"We hope to find treatment methods within molecular medicine that either block or activate the brain's response to infections," summarises Line Reinert.

The research results – more information:

 

The research is basic research.

The research group comprises 21 members, with ten of them coming from the Department of Biomedicine. The study is headed by Associate Professor Line S. Reinert and carried out with the help of researchers in Sweden and the Netherlands, as well as researchers at the University Hospital in Skejby, Aarhus. 

The research is carried out with support from the Lundbeck Foundation and the Danish Council for Independent Research.

Link to the article in the Journal of Clinical Investigation

Contact:

Line S. Reinert is an associate professor at the Department of Medical Microbiology and Immunology. 
Aarhus Universitet, Health, Institut for Biomedicin
Direct tel.: (+45) 3064 2210
  Email: line.reinert@biomed.au.dk