The cytokine MIF, produced by macrophages in response to malarial hemozoin (black), triggers anemia in the infected host.

A study on page 1185 shows that the immune system's attempt to fight off malaria-causing parasites triggers severe anemia, a lethal complication of the disease. Parasite-induced synthesis of the cytokine MIF (migration inhibitory factor), say McDevitt and colleagues, decreases the production of red blood cells (RBCs) from the bone marrow.

Parasites of the Plasmodium genus use host RBCs as multiplication factories, rupturing the cells as progeny parasites exit. Plasmodium infection also hampers the production of new RBCs from the bone marrow, an effect this group recently attributed to MIF, which is produced by macrophages that ingest infected RBCs. MIF helps activate T cells and is required to combat other infectious microbes including Salmonella and Leishmania.

But in malaria, MIF works against the host (although it probably also has benefits). In their new study, McDevitt et al. confirm MIF as the culprit of malarial anemia by showing that parasite-infected mice that lack MIF were less anemic and survived longer than wild-type mice. In vitro, the cytokine both suppressed the differentiation of RBCs from progenitor cells and decreased their hemoglobin content, possibly as a result of disrupted ERK–MAPK signaling in these cells.

Monocytes from humans carrying known “high producer” MIF gene polymorphisms secreted more MIF in response to the malarial pigment hemozoin than did those from individuals without this allele. And this group recently found a high prevalence of the low producer genotype among malaria-infected people in endemic regions of Africa, perhaps the result of an evolutionary survival advantage of keeping MIF levels low.

Population studies are now underway to determine whether MIF levels influence susceptibility to or severity of malaria in humans. In the meantime, synthetic inhibitors of MIF–currently in clinical development–might provide an effective alternative to the costly (and risky) blood transfusions currently used to treat malarial anemia.