Molecular Epidemiology Study And Functional Characterization Of Macrophage Migration Inhibitory Factor Derived From Malaria Parasites

Macrophage migration inhibitory factor (MIF) was a pluripotent cytokine, and ubiquitously expressed in a variety of cells, such as macrophages and lymphocytes. It exhibited an array of biological functions ranging from immune responsiveness to cell growth and induced inflammation at the interface between the innate immunity and acquired immunity. Host-derived MIF has been implicated in the pathogenesis of malaria infection, especially in malarial anemia. Recently, three Plasmodium parasite-derived MIFs, P. falciparum MIF (PfMIF), P. berghei MIF (PbMIF) and P. yoelii MIF(PyMIF), were suggested to modulate host immune-cell activity. However, the precise roles of these parasite-derived MIFs during malaria infection remain unknown.In this study, we have investigated two Plasmodium parasites derived MIFs in peripheral blood of malaria patients and analyzed their correlations with several major factors during malaria infection. We found both P. falciparum MIF (PfMIF) and P. vivax MIF (PvMIF) levels in patients were positively correlated with parasitemia, TNF-a, IL-10 and MCP-1, but not correlated with TGF-β1 and IL-12. Of interest was that PvMIF levels was positively correlated with host body temperature and HuMIF concetrations. Moreover, multiple stepwise regression analysis also showed that parasitemia, IL-10, and HuMIF expression were significant predictors of Plasmodium MIFs production. Furthermore, whether the patients were co-infected with other infectious disease (eg., HIV, HCV or HBV) did not affect the levels of Plasmodium MIF in plasma. In addition, during anti-malaria drug treatment, Plasmodium MIFs concentration decreases were followed by parasitemia in most of the patient samples. Our results suggested that Plasmodium parasite MIF circulating level was a reflection of parasitemia, and was thus closely correlated with malaria disease severity. Therefore, as such, this factor could be a promising disease predictor and applicable in clinical diagnosis.According to the work above, we proved that Plasmodium parasite MIFs were involved in host immune response using molecular epidemiology methods. Further, the effect of another parasite homologue of MIF (PyMIF) on mouse bone marrow dendritic cells (BM-DCs) was investigated and compared the effect of its murine counterpart (MmMIF). The results showed that, PyMIF could reduce the surface expression of Toll-like receptor (TLR) 4, but not induce BM-DCs maturation or inhibit the maturation of BM-DC to LPS stimuli. We also investigated the effect of BM-DCs (previously incubated with PyMIF) on CD8+T cells, the results showed that such BM-DCs could reduce CD8+T cells surface expression of CD69; whereas, they could not modulate the secretion of IL-2 and CTL response.In this study, the relationships between Plasmodium parasite MIFs and host immune system during malaria infection were investigated in terms of in vivo epidemiology and in vitro cell biology. The work confirmed that Plasmodium parasite MIF circulating levels closely correlated with malaria disease severity and provided important data in understanding the relationships between Plasmodium and the host immune response.