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 a Plasmodium MIF (PMIF). Like human MIF, histidine-tagged purified recombinant PMIF shows tautomerase and oxidoreductase activities (although the activities are reduced compared to those of histidinetagged human MIF) and efficiently inhibits AP-1 activity in human embryonic kidney cells. Furthermore, we found that Plasmodium berghei MIF 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. Mutant P. berghei parasites lacking PMIF 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 that PMIF is produced by the parasite to influence host immune responses and the course of anemia upon infection.

Elevated Levels of thePlasmodium yoeliiHomologue of Macrophage Migration Inhibitory Factor Attenuate Blood-Stage Malaria

“…Studies of P. berghei-, P. falciparum-, and P. yoelii-encoded MIF revealed a 116-amino-acid protein with ϳ30% amino acid sequence identity with mMIF (2,22,24,52). Collectively, the data suggest that plasmodial MIF (pMIF) is structurally similar to mMIF and possesses some but probably not all activities normally attributed to mMIF.…”

“…An explanation for the apparent discrepancies is not obvious. One factor not specifically considered in those previous studies is that all genomes of Plasmodium parasites examined to date also contain mif homologues (2,29).…”

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

“…3 B and C). To investigate better the role of PbMIF during blood-stage malaria, we also studied the macrophage response to a strain of PbA with a genetic deletion in PbMIF (mifKO PbA) (36). Peritoneal macrophages were harvested from naive mice, activated with IFN-γ, and stimulated in vitro with magnetically purified PbA-infected red blood cells (iRBCs) obtained from WT PbA-or mifKO PbA-infected mice.…”

ALeishmaniaOrtholog of Macrophage Migration Inhibitory Factor Modulates Host Macrophage Responses

“…The tick vector responsible for the transmission of anaplasmosis, Amblyomma americanum, produces an MIF ortholog that is expressed in the salivary gland (9). MIF-like proteins also have been reported recently in pathogenic species of Eimeria (10), Trichinella (11), and Plasmodium (12,13), and the question has been raised as to whether these proteins play a role in the parasite-host interaction.…”