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  • Title: Elevated levels of the Plasmodium yoelii homologue of macrophage migration inhibitory factor attenuate blood-stage malaria.
    Author: Thorat S, Daly TM, Bergman LW, Burns JM.
    Journal: Infect Immun; 2010 Dec; 78(12):5151-62. PubMed ID: 20837716.
    Abstract:
    The excessive production of proinflammatory cytokines plays a significant role in the pathogenesis of severe malaria. Mammalian macrophage migration inhibitory factor (MIF) (mMIF) is an immune mediator that promotes a sustained proinflammatory response by inhibiting the glucocorticoid-mediated downregulation of inflammation. In addition, Plasmodium parasites also encode a homologue of mammalian MIF that is expressed in asexual-stage parasites. We used the Plasmodium yoelii murine model to study the potential role of parasite-encoded MIF in the pathogenesis of malaria. Antibodies raised against purified, non-epitope-tagged P. yoelii MIF (PyMIF) were used to localize expression in trophozoite- and schizont-stage parasites and demonstrate extracellular release. In vitro, recombinant PyMIF was shown to actively induce the chemotaxis of macrophages but did not induce or enhance tumor necrosis factor alpha (TNF-α) production from peritoneal macrophages. To examine the role of parasite-derived PyMIF in vivo, two transgenic parasite lines that constitutively overexpress PyMIF were generated, one in a nonlethal P. yoelii 17X background [Py17X-MIF(+)] and the other in a lethal P. yoelii 17XL background [Py17XL-MIF(+)]. Challenge studies with transgenic parasites in mice showed that the increased expression of PyMIF resulted in a reduction in disease severity. Mice infected with Py17X-MIF(+) developed lower peak parasitemia levels than controls, while malaria-associated anemia was unaltered. Infection with Py17XL-MIF(+) resulted in a prolonged course of infection and a reduction in the overall mortality rate. Combined, the data indicate that parasite-derived MIF does not contribute significantly to immunopathology but, through its chemotactic ability toward macrophages, may attenuate disease and prolong infection of highly virulent parasite isolates.
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