10:23am Sunday 22 October 2017

Iron regulators join fight against pathogens

Humans – along with all living organisms, including pathogens – need iron to survive: invading organisms try to highjack it from their hosts in order to thrive and multiply. Researchers at EMBL Heidelberg, and their colleagues, have now discovered that proteins responsible for helping the body maintain the correct levels of iron at a cellular level are also involved in helping to prevent this theft. These proteins form a system called IRP/IRE (iron regulatory protein/iron responsive element).

“The work we’ve been doing has uncovered a connection between two very important functions that are typically seen as separate: the body’s innate immune system, and its iron metabolism,” explains Matthias Hentze, co-author of the paper and Director of EMBL.

The team analysed how mice reacted to an infection by the Salmonella bacteria, depending on whether they had a functional IRP/IRE system or not. Mice lacking a functional IRP/IRE system from professional immune cells called macrophages did well as long as they were not infected, but when the Salmonella bacteria were introduced, they died. This showed that the iron regulatory system was crucial for the macrophages, the target-cells for this specific pathogen, to fight off the infection effectively.

“Withholding iron from an invading pathogen is an innate defence against infection“, explains Bruno Galy, former Staff Scientist at EMBL-Heidelberg and currently group leader in the research division “Virus-Associated Carcinogenesis” of the German Cancer Research Centre (DKFZ) “Our study reveals that the IRP/IRE system plays an important role in this defence.”  

The precise mechanisms through which the IRP/IRE system works in the macrophages will need further investigation, although the researchers have a number of theories.

One theory is that the IRP proteins help the macrophages produce a molecule called lipocalin 2, which is known to block bacteria from taking up iron from its host. Another idea is that the IRP/IRE system represses the expression of a protein called ferritin. Ferritin is present in cells as a kind of compartment to store iron until it is needed. Invading bacteria get access to these iron supplies and if the IRP proteins are not present, the cell will store much more iron than required – thus providing valuable nutrients for invaders.

The research was carried out in partnership with Guenter Weiss and colleagues at the Medical University of Innsbruck and Ferric Fang at the University of Washington.

The group now plans to carry out further investigations to find out if the IRP/IRE system is also important for other types of bacteria, and other types of infection, such as viruses or parasites. They also hope to discover if the IRP/IRE system has a role to play in other types of immune response, such as inflammation. This immune response is implicated in the progress of human diseases such as cancer or atherosclerosis so a better understanding of its mechanisms could have implications for research into new treatments.

Manfred Nairz, Dunja Ferring-Appel, Daniela Casarrubea, Thomas Sonnweber, Lydie Viatte, Andrea Schroll, David Haschka, Ferric C. Fang, Matthias W. Hentze, Guenter Weiss, and Bruno Galy: Iron Regulatory Proteins Mediate Host Resistance to Salmonella Infection: CELL Host & Microbe 2015. DOI: 10.1016/j.chom.2015.06.017 

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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