Functional Characterization of thePlasmodium falciparumandP. bergheiHomologues of Macrophage Migration Inhibitory Factor

Abstract

Macrophage migration inhibitory factor (MIF) is a mammalian cytokine that participates in innate and adaptive immune responses. Homologues of mammalian MIF have been discovered in parasite species infecting mammalian hosts (nematodes and malaria parasites), which suggests that the parasites express MIF to modulate the host immune response upon infection. Here we report the first biochemical and genetic characterization of aPlasmodiumMIF (PMIF). Like human MIF, histidine-tagged purified recombinantPMIF shows tautomerase and oxidoreductase activities (although the activities are reduced compared to those of histidine-tagged human MIF) and efficiently inhibits AP-1 activity in human embryonic kidney cells. Furthermore, we found thatPlasmodium bergheiMIF is expressed in both a mammalian host and a mosquito vector and that, in blood stages, it is secreted into the infected erythrocytes and released upon schizont rupture. MutantP. bergheiparasites lackingPMIF were able to complete the entire life cycle and exhibited no significant changes in growth characteristics or virulence features during blood stage infection. However, rodent hosts infected with knockout parasites had significantly higher numbers of circulating reticulocytes. Our results suggest thatPMIF is produced by the parasite to influence host immune responses and the course of anemia upon infection.