Understanding the mechanisms of infection

What actually happens in the body’s cells when they are invaded by dangerous bacteria and parasites? Christian Hedberg is using the Legionnaires’ bacterium, among other things, to examine key biochemical mechanisms in the infection process. His hope is that his research will result in new, more effective medicines.

Christian Hedberg

PhD in Organic Chemistry

Wallenberg Academy Fellow 2013

Institution:
Umeå University

Research field:
A biochemical biology approach to understanding intracellular infection processes.

In summer 2014 Christian moved from Dortmund in Germany to Umeå. He brought with him all his research from the Max Planck Institute of Molecular Physiology, including three German researchers and some instruments.

“Umeå University has made a great effort to ensure that everything goes as well as possible. I am very impressed with the research being carried out here. The greatest challenge I face is probably settling into the Swedish system,” Christian says.

He stresses that without the support of the Knut and Alice Wallenberg Foundation, this full-scale recruitment would not have been possible.

“I was also able to take the money I had received from the German Research Council (DFG) to Sweden. All major research funding bodies in Europe are party to an agreement on ‘grant money mobility’. It’s a very efficient system.”

“The grant is unique and represents a fantastic opportunity. If I had not become a Fellow, I would probably have remained in Germany. This was arguably the only chance I had of coming back to Sweden, and it was the last chance to become a Fellow, because I was about to reach the age limit for nomination.”

From cancer to infections

Christian tells how he attended the Max Planck Institute as a postdoc in 2006, having gained a PhD in organic chemistry at Uppsala University. The aim of his stay there was to broaden his expertise to encompass applications of organic chemistry within the biological field.

“After three years I set up my own team. At that time we focused primarily on cancer, which was in line with the overall profile of the institute. After a while, in parallel with my cancer research, I began to study new applications for the methods we had, realizing there was a great deal we could do in the field of infection.”

The aim of Christian’s research is to learn more about the chemical processes taking place within cells when they are infected by pathogens such as bacteria and parasites. He hopes that this knowledge will ultimately be a key element in the development of new medicines.

“At the moment we know very little about how infections occur at the intracellular level; there is untrodden ground to be explored. The unique element of my research is that we are looking at the chemistry involved in infections. There is very little research in this area.”

What Christian is looking for in the newly fitted out chemistry lab, and in various animal experiments, are mechanical similarities between the way different organisms ‘kidnap’ and modify the host cell during infection. Similarities are carefully structured and systematized.

“Bacteriologists focus more on genetic similarities, and many of them think what I am doing is a very strange. But infection research has a tendency to tread water, and needs a push to move forward. We are now lining up several of these intracellular pathogens side by side, and comparing them. Here in Umeå we have access to support from many strong areas of infection research.”

Starting with Legionnaires’

Some of Christian’s research concern the Legionella pneumophila bacterium, and a pernicious parasite called Cryptosporidium. Legionella is the cause of Legionnaires’ disease, a form of pneumonia. Cryptosporidium, which is found in drinking water and elsewhere, causes violent diarrhea in animals and humans. Cryptosporidiosis is an intestinal disease that can be life-threatening for people with a weakened immune system.

Christian explains that Legionella is a ‘gram negative’ bacterium with thin cell walls, and was chosen because it is fairly easy to work with.

“It can be genetically modified, and it grows nicely in a test tube. When I began studying Legionella I realized there could be similarities with other intracellular pathogens.”

Triggering the digestion mechanism

The cells in the immune system that are invaded by the Legionella bacterium are called macrophages. Once inside the cell, the bacterium releases hundreds of proteins, which modify the macrophage’s own proteins and take charge of the cell.

“Legionella wants to be engulfed by macrophages so that it can reproduce. We have recently found small molecules on the bacterium that trigger the digestion mechanism of these macrophages. This knowledge is essential to understanding the intracellular processes involved in infection,” says Christian.

His cryptosporidiosis research is being conducted in collaboration with researchers at Inra – the French National Institute for Agricultural Research. The parasites used in the study are cultured at Inra in the stomachs of calves, and are stored in freezers at the lab here in Umeå. One calf provides enough material for about one year’s research.

It is known that an enzyme that catalyzes lipid formation is essential if the infection is to gain a hold in the host cell. The research team has tested an existing drug that triggers fatty acid metabolism in the cells, and has achieved good results in mice and piglets carrying the parasite.

“The drug prevents the ‘crypto’ from receiving the right sort of fatty acids from the host cell, and it dies. Now we are looking for even more effective fatty acid synthesis inhibitors in the substance libraries of pharmaceutical companies. If we can inhibit the formation of the fatty acids that the parasite needs, it is doomed.”

Text Susanne Rosén
Translation Maxwell Arding
Photo Magnus Bergström