text: Pathogenic bacteria and fungi have developed the means of survival in animal tissue. They may invade the gastro-intestinal tract (Escherichia, Shigella and Salmonella), the lung (Pseudomonas, Bordetella, Streptococcus and Corynebacterium), skin (Staphylococcus) or the urinary tract (Escherichia and Pseudomonas). Such bacteria may colonise wounds (Vibrio and Staphylococcus) and be responsible for septicaemia (Yersinia and Bacillus). Some bacteria survive for long periods of time in intracellular organelles, for instance Mycobacterium. (see table). Because of this continual risk of bacterial and fungal invasion, animals have developed a number of lines of defence based on immunological strategies, the complement system, the production of iron–siderophore binding proteins and the general "withdrawal" of iron.
  There are two major types of iron-binding proteins present in most animals that provide protection against microbial invasion – extracellular protection is achieved by the transferrin family of proteins and intracellular protection is achieved by ferritin. Transferrin is present in the serum at approximately 30 μM, and contains two iron-binding sites, each with an extremely high affinity for iron. Under normal conditions it is about 25–40% saturated, which means that any freely available iron in the serum will be immediately scavenged – thus preventing microbial growth. Most siderophores are unable to remove iron from transferrin. Mammals also produce lactoferrin, which is similar to serum transferrin but possesses an even higher affinity for iron. Lactoferrin is present in secretory fluids, such as sweat, tears and milk, thereby minimising bacterial infection.
  Ferritin is present in the cytoplasm of cells and limits the intracellular iron level to approximately 1 μM. Ferritin is a much larger protein than transferrin and is capable of binding several thousand iron atoms in a nontoxic form. Siderophores are unable to directly mobilise iron from ferritin.
  In addition to these two classes of iron-binding proteins, a hormone, hepcidin, is involved in controlling the release of iron from absorptive enterocytes, iron-storing hepatocytes and macrophages. Infection leads to inflammation and the release of interleukin-6 (IL-6 ) which stimulates hepcidin expression. In humans, IL-6 production results in low serum iron, making it difficult for invading pathogens to infect. Such iron depletion has been demonstrated to limit bacterial growth in both extracellular and intracellular locations.
  In addition to "iron withdrawal" tactics, mammals produce an iron –siderophore binding protein, siderochelin. Siderochelin is a member of the lipocalin family of proteins, which while diverse in sequence, displays a highly conserved structural fold, an 8-stranded antiparallel β-barrel that forms a binding site with several adjacent β-strands. Siderocalin (lipocalin 2) has 3 positively charged residues also located in the hydrophobic pocket, and these create a high affinity binding site for iron(III)–enterobactin. Siderocalin is a potent bacteriostatic agent against E. coli. As a result of infection it is secreted by both macrophages and hepatocytes, enterobactin being scavenged from the extracellular space.