The iron storage protein ferritin in bacterial infection

Iron is an essential trace element centrally involved in the production of blood cells, the supply with energy, the division of cells and numerous other functions and metabolic pathways in the human body. Ferritin is the sole protein known for iron storage. Most cell types produce ferritin but the largest quantities are found in certain immune cells known as macrophages. Macrophages secrete ferritin into the blood stream. Thereafter, ferritin can be measured in a blood sample to evaluate the iron supply of the human body. The production of ferritin is induced both in response to iron excess and during infections. Presumably, the latter is the basis of an immune mechanism which aims at withholding iron from invading bacteria. A sufficient access to the nutrient iron not only maintains human metabolic functions, it is also required for the growth and proliferation of bacteria. Therefore, the uptake of iron into macrophages and its incorporation into ferritin are sophisticated strategies of host defense. On the other hand, we assume that certain intracellular bacteria are able to degrade ferritin and use it as an iron source. The interactions between ferritin, the function of the immune system including macrophages and the growth of bacteria are incompletely understood. The current FWF project aims at comprehensively characterizing ferritins functions in infections with intracellular and extracellular bacteria.

Iron is an essential nutrient required for blood formation, cell division and many other functions and metabolic processes in the human body. Ferritin is a central protein in iron metabolism that stores iron, thereby neutralising its toxic effects. It is produced by most cells in the body, with particularly high levels found in the phagocytic cells of the immune system called macrophages. Depending on the iron load in the storage cells, iron is released into the bloodstream, where it can be measured. Ferritin is produced in excess not only when there is a surplus of iron, but also during bacterial infections. Iron is essential for both bacterial growth and host immune defence. To limit the availability of iron to pathogenic microorganisms, host organisms use a mechanism known as "nutritional immunity". This involves storing iron in proteins such as ferritin, thereby reducing its availability to pathogenic microorganisms. On the other hand, there is evidence that certain intracellular bacteria, such as Listeria or Salmonella, can degrade ferritin and use it as a source of iron. However, the exact mechanisms by which these microbes access ferritin-associated iron and the interactions between ferritin, macrophage immune defence and bacterial replication machinery are not well understood. The aim of the current FWF project was to comprehensively elucidate the effects of ferritin on bacterial growth and its immunoregulatory role in infections with extracellular and intracellular bacteria. Our studies have shown that ferritin-bound iron is less available to bacteria than free ionic iron, but still significantly promotes bacterial growth. The availability of ferritin-bound iron is influenced by bacterial genes involved in iron uptake. In addition, enzymes such as superoxide dismutase, which protect cells from oxidative stress, affect bacterial growth and inhibit iron uptake through siderophore-independent mechanisms. Our results suggest that ferritin H in the host is important for macrophage immune defence to control infections with bacteria such as Salmonella. Defects in macrophage ferritin function can lead to increased infection, reduced iron storage capacity and increased inflammatory activity. A better understanding of the interactions between ferritin, iron metabolism, nutritional immunity and bacterial infections may provide new therapeutic approaches for the treatment of infectious diseases.