FIGURE 1.

Hypotheses for the effect of co-infections on iron metabolism. (A) Possible implications of blood-stage malaria infection on host susceptibility to other infections. Blood-stage parasitemia causes hepcidin upregulation, which in turn routes iron away from hepatocytes and lowers serum iron levels, blocking the erythron’s access to iron and causing anemia. Lowered hepatocyte iron levels prevent the establishment of a second malaria infection (superinfection) by blocking liver-stage growth. Hepcidin also causes iron levels to increase in macrophages and potentially in enterocytes as well, thus possibly giving an advantage to pathogens that exploit the macrophage niche (non-typhoidal salmonella, tuberculosis, Toxoplasma) and those that require iron in enterocytes (Toxoplasma). (B) Hypothesized effect of HCV infection on malaria susceptibility. Long-term HCV infection causes hepcidin suppression, thus increasing liver iron stores and plausibly increasing malaria susceptibility. (C) Potential impact of intestinal helminth infection. Helminths cause periodic blood loss, which restricts iron to the liver, potentially blocking malaria liver-stage infection as in (A). Decreases in serum restrict iron availability for erythropoiesis, causing anemia, which in turn causes the downregulation of hepcidin.