Plasma Concentration of Malaria Parasite-Derived Macrophage Migration Inhibitory Factor in Uncomplicated Malaria Patients Correlates with Parasitemia and Disease Severity

Abstract

Host macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of malaria infections. Several Plasmodium parasite-derived MIFs were identified to have the potential to regulate host immune response. However, the role of Plasmodium MIFs in the immunopathogenesis of malaria infection and the relationships between these mediators and inflammatory cytokines remained unclear. In this study, we have investigated two Plasmodium MIFs in peripheral blood of uncomplicated malaria patients and analyzed their correlations with several major factors during malaria infection. We found that both Plasmodium falciparum MIF (PfMIF) and Plasmodium vivax MIF (PvMIF) levels in patients were positively correlated with parasitemia, tumor necrosis factor alpha, interleukin-10 (IL-10), and monocyte chemoattractant protein 1 but were not correlated with transforming growth factor ␤1 and IL-12. Of interest was that the PvMIF level was positively correlated with host body temperature and human MIF (HuMIF) concentrations. Moreover, multiple stepwise regression analysis also showed that parasitemia, IL-10, and HuMIF expression were significant predictors of Plasmodium MIF production. In addition, during antimalarial drug treatment, the decreasing of Plasmodium MIF concentrations was followed by parasitemia in most patients. Our results suggested that the Plasmodium MIF circulating level reflects the level of parasitemia and thus was closely correlated with disease severity in uncomplicated malaria. Therefore, this factor has the potential to be a promising disease predictor and is applicable in clinical diagnosis.

Plasmodium yoelii Macrophage Migration Inhibitory Factor Is Necessary for Efficient Liver-Stage Development

“…During blood-stage replication, Plasmodium MIF is expressed in trophozoites and schizonts and is released during schizont rupture (2,16,39). It has been reported that Pf-MIF localizes to Mauer's clefts and is detectable in the cytoplasm of the host erythrocyte (11); however, this localization was not observed with Py-MIF, which was detected only in the parasite cytoplasm (45).…”

“…Accordingly, antibodies against parasite MIF have been isolated from sera of both previously and currently infected hosts (11,45). P. falciparum MIF (Pf-MIF) has also been detected in the blood of infected patients (2,16,39). In addition, it was shown that Plasmodium MIF conserves the chemotactic but not cytokine functions of mammalian MIF (2,45).…”

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

“…MIF is a potent inhibitor of erythroid differentiation, and it may suppress erythropoietin-dependent erythroid colony formation and hemoglobin production (108). The role of MIF in plasma from uncomplicated P. vivax malaria patients has been investigated, and its levels have been positively associated with parasite density but not with hematological parameters (109).…”

Parasite virulence, co-infections and cytokine balance in malaria

“…43 Moreover, a prominent regulatory response can be simultaneously found in acute vivax malaria, with median plasma concentrations of IL-10 up to eight-fold greater than those measured in falciparum or mixed-species malaria patients living in the same area of endemicity. 43,46 Accordingly, higher IL-10/TNF-alpha, IL-10/IFN-gamma, and IL-10/IL-6 ratios are found in uncomplicated vivax malaria, compared to uncomplicated falciparum or mixed-species malaria, 43 consistent with a bias toward regulatory cytokines in human immune responses to P. vivax. An IL-10-dominated environment prevents excessive inflammation but may theoretically favor parasite multiplication.…”

“…In fact, plasma concentrations of IL-10/TNF-alpha and IL-10/IFN-gamma ratios correlate positively with P. vivax parasitemias 41,43,47,48 and return to their normal range after antimalarial treatment. 43,46,49 Interestingly, however, high IL-10 levels do not eventually translate into overwhelming parasitemias, since P. vivax blood stages can only infect reticulocytes, which comprise less than 1% of the circulating pool of red blood cells.…”