Strategic Communication and Public Relations

Iron regulators join fight against pathogens

No. 33c2 | 17/07/2015 | by Koh

Proteins responsible for controlling levels of iron in the body also play an important role in combatting infection, according to a study published today in Cell Host & Microbe.

Fluorescence microscopy picture of bone marrow-derived macrophages: red: macrophage marker / blue: DNA /green: ferritin.
© Bruno Galy (DKFZ)

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.” 

© Petra Riedinger (EMBL)

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 institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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