Immune Molecule Defends Against Bacterial Infection by Withholding Iron
An international group of researchers has found, in a mouse model, one way in which the body thwarts infection by pathogenic bacteria: an immune molecule called IL-22 activates proteins in the blood to limit availability of iron, which bacteria need. In humans and other animals, most of the body’s iron is concentrated in structures called heme groups within hemoglobin inside red blood cells, which carry out the vital function of ferrying oxygen from the lungs to sites around the body. Iron is also an essential nutrient for microorganisms, and the body naturally limits bacterial access to the nutrient as a defense against infection in a process called “nutritional immunity.” Some pathogens in the circulation circumvent the scarcity of free iron in the blood by attacking red blood cells, causing them to release their iron-rich hemoglobin and heme groups.
Researchers set out to discover whether nutritional immunity involved limiting bacterial access to the major iron stores contained in the heme groups and blood cell hemoglobin. They focused their efforts on one immune system molecule in particular called interleukin-22 (IL-22), which is known for its role in protecting against bacterial infection. Using a mouse model, they tested how the presence or absence of IL-22 affected infection with two pathogenic bacteria—Citrobacter rodentium, a major pathogen in mice, and Escherichia coli, a leading cause of blood infection in humans. Mice that had been genetically altered to lack IL-22 were much more likely than normal mice to die from C. rodentium infection due to greater pathogen burden in the blood. While analyzing changes in blood protein levels during infection, the scientists noticed that the infected mice without IL-22 had much lower amounts of two proteins in the blood, called hemopexin and haptoglobin. These proteins are produced mainly by the liver and bind to free heme and hemoglobin, respectively, that are released during an infection, thereby limiting their toxicity to other host cells. The IL-22-deficient mice also had more free hemoglobin in the blood after infection, indicating more activity by the bacteria in attacking blood cells. Replacing IL-22 in the deficient mice with an intravenous infusion helped their blood proteins fight the infection in the animals and in cell culture by boosting levels of the heme-binding hemopexin. Similar results were found when the human pathogen E. coli was used instead of C. rodentium.
This work shows how the immune molecule IL-22 helps protect animals against bacterial infection in the blood through raising hemopexin levels and limiting the availability of heme. Further studies may seek to understand how these bacterial pathogens are able to access the iron contained within heme. Future applications of nutritional immunity may capitalize on this knowledge to develop new treatments for bacterial infections in the blood using IL-22, hemopexin, or another protein that limits heme availability.