The irony of host defense

Macrophages from flatiron mice, with functional defects in the iron exporter ferroportin, support increased bacterial growth when infected by Chlamydia psittaci, Chlamydia trachomatis, and Legionella pneumophila. The oral iron chelators deferriprone and desferasirox reduced intracellular bacterial growth, suggesting a new approach to antimicrobial therapy.

Iron is essential for both pathogenic microbes and their hosts. Bacterial infections are often associated with a reduction in circulating iron, a calibrated host defense mechanism that deprives microorganisms of a nutrient required for their growth and virulence. The recent elucidation of the function of the iron regulator hepcidin suggests that the molecular basis for the hypoferremia of infection resides in the ability of this liver hormone to bind and down-regulate the iron exporter ferroportin,¹  thereby reducing extracellular iron availability to pathogens.

The role of ferroportin's iron export function in macrophages poses a unique dilemma, because the hepcidin response is predicted to increase intracellular iron in cells of the reticuloendothelial system. Thus, although growth of extracellular bacteria may become limited by host iron sequestration, obligate intracellular pathogens that reside within macrophages could potentially find a rich supply of iron. In this issue of Blood, Paradkar and colleagues took advantage of flatiron mice, a strain heterozygous for a loss-of-function ferroportin mutation, to study growth of the intracellular pathogens Chlamydia and Legionella, both of which require iron for replication. Compared with macrophages from control mice, flatiron macrophages supported enhanced microbial growth. In addition, Paradkar and coworkers found that exogenous hepcidin promoted bacterial growth in control macrophages, consistent with the idea that loss of ferroportin's iron export activity is associated with increased infection. Importantly, flatiron macrophages did not respond to hepcidin. These observa-tions imply that certain bacterial infections may be promoted by intracellular iron retention due to loss-of-ferroportin iron export activity and/or its regulation by hepcidin in human patients with ferroportin disease, a type of hereditary hemochromatosis.¹ 

The new data are consistent with previous studies showing that changes in ferroportin expression and intracellular iron levels can influence growth of Salmonella^2,3  and Mycobacteria.⁴  Combined, this body of research points to a close association between macrophage iron export by ferroportin, intracellular iron retention, and infection by obligate intracellular pathogens. Using 2 oral iron chelators recently approved for human use, Paradkar et al further tested the possible therapeutic application of reducing macrophage iron levels. Both deferriprone and desferasirox reduced bacterial growth in control and flatiron macrophages, raising the possibility that these drugs might be effective in treating bacterial infections. However, caution is warranted; although iron supplementation may be detrimental to disease outcome, manipulation of iron status to deplete the host's supply could result in adverse consequences due to iron deficiency induced outside of the body's normal regulatory responses. Clearly, further study is needed to evaluate the ability of oral iron chelators to modulate host defense and infection. As a ferroportin disease model, flatiron mice may shed light on using this approach in at least one important clinical setting—hereditary hemochromatosis—wherein regulation of iron status by the hepcidin/ferroportin axis can be disrupted.