10 Iron and infection TIMOTHY E. A. PETO CHAIM HERSHKO Iron is an essential element for most living organisms. Micro-organisms therefore have to compete with their host for their iron supply. In order to understand the relationship between pathogen and host it is essential to consider the basic chemistry and biochemistry of iron. Briefly, oxidized (ferric) iron, at neutral pH, is insoluble. Thus any organism utilizing environmental, or inorganic, iron requires a mechanism to solubilize it before it can be assimilated. Micro-organisms and plants use low molecular weight chelators, such as citrate or siderophores, for this purpose. Animals cannot absorb insoluble inorganic iron but require it to be solubilized, usually by plants, micro-organisms or other animals, before it can be used. Once ingested the iron is kept soluble by the use of haem or iron binding proteins such as transferrin, lactoferrin or ferritin. The storage and transport iron binding proteins have a very high affinity for iron. This may appear at first sight to be surprising because the high affinity might be thought to reduce the availability of iron for the main iron-containing compounds. However, these high affinity ligands render the iron non-toxic as it cannot catalyse the formation of hydroxyl radicals via Fenton chemistry. Also, as is discussed in this chapter, these ligands may compete successfully with many potential invading pathogenic organisms. Hypoferraemia is one of the most constant features of infectious disease. Since iron deprivation in bacterial cultures is regularly associated with inhibition of growth, it has been suggested that hypoferraemia may repre- sent an important defence mechanism. The term 'nutritional immunity' was coined by Kochan (1973) to underline the importance of iron deprivation as a key mechanism limiting the growth of invading organisms. Within the last decade a number of reviews have been published on the relation between infection and iron availability (Weinberg, 1974; Weinberg, 1975; Pearson and Robinson, 1976; Weinberg, 1978; Bullen, 1981; Finkelstein et al, 1983; Oppenheimer and Hendrickse, 1983; Ward, 1986; Hershko et al, 1988). Although the nutritional immunity hypothesis has been enthusiastically adopted in some of these, others (Pearson and Robinson, 1976; Oppen- heimer and Hendrickse, 1983; Huebers and Finch, 1987; Hershko et al, 1988) have underlined the paucity of clinical, as against experimental, data supporting the significance of iron deficiency or overload in determining the severity or prevalence of infectious disease in humans. Bailli~re's ClinicalHaematology--Vol. 2, No. 2, April 1989 435