Characterisation of macrophage migration inhibitory factor homologues in plasmodium species

Abstract

Malaria is responsible for 1-3 million deaths per year worldwide, with half the global population at risk of infection. Plasmodium falciparum is the parasite responsible for severe malaria and accounts for almost all fatal cases. The Plasmodium falciparum genome sequencing project identified a putative protein that shares sequence homology with the cytokine macrophage migration inhibitory factor (MIF). MIF has been shown to have a wide range of functions including the modulation of inflammatory responses. The major objective of this project was to characterise the potential MIF homologue in P. falciparum (PfMIF) and to test the hypothesis that this protein may influence the host immune system during the course of P. falciparum infection. Sequence analysis and modelling techniques were used to show that PfMIF shares important structural similarities to other MIF species. Studies of parasites in culture demonstrated that PfMIF mRNA and protein are expressed during ring and trophozoite stages of the parasite life cycle. Furthermore, PfMIF was found to be exported into the cytosol of the infected erythrocyte, and released upon schizont rupture, thus providing an opportunity for PfMIF to interact directly with the host immune system. Recombinant PfMIF protein was generated and used to treat monocytes in vitro. These experiments showed that PfMIF inhibits the random migration and chemotaxis of monocytes and influences surface molecule expression, as evidenced by a decrease in TLR2, TLR4 and CD86. Access to a cohort of children in Kenya allowed examination of patient antibody responses to PfMIF, which showed a pattern of expression similar to antibody responses to other malaria antigens previously examined. In conclusion, these studies suggest that PfMIF could be an important molecule involved in the interaction between the parasite and the host immune system during the course of P. falciparum infection.