Characterization of a Plasmodium falciparum Macrophage-Migration Inhibitory Factor Homologue

Journal of Infectious Diseases, Mar 2007

Background. Macrophage-migration inhibitory factor (MIF), one of the first cytokines described, has a broad range of proinflammatory properties. The genome sequencing project of Plasmodium falciparum identified a parasite homologue of MIF. The protein is expressed during the asexual blood stages of the parasite life cycle that cause malarial disease. The identification of a parasite homologue of MIF raised the question of whether it affects monocyte function in a manner similar to its human counterpart. Methods. Recombinant P. falciparum MIF (PfMIF) was generated and used in vitro to assess its influence on monocyte function. Antibodies generated against PfMIF were used to determine the expression profile and localization of the protein in blood-stage parasites. Antibody responses to PfMIF were determined in Kenyan children with acute malaria and in control subjects. Results. PfMIF protein was expressed in asexual blood-stage parasites, localized to the Maurer's cleft. In vitro treatment of monocytes with PfMIF inhibited random migration and reduced the surface expression of Toll-like receptor (TLR) 2, TLR4, and CD86. Conclusions. These results indicate that PfMIF is released during blood-stage malaria and potentially modulates the function of monocytes during acute P. falciparum infection.

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Characterization of a Plasmodium falciparum Macrophage-Migration Inhibitory Factor Homologue

Damien V. Cordery 2 3 Uday Kishore 0 2 Sue Kyes 1 2 Mohammed J. Shafi 2 4 Katherine R. Watkins 2 3 Thomas N. Williams 2 4 Kevin Marsh 2 4 Britta C. Urban () 2 3 0 Laboratory of Human Immunology, Division of Biosciences, School of Health Sciences and Social Care, Brunel University , West London , United Kingdom 1 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital , Oxford 2 Received 28 July 2006; accepted 13 October 2006; electronically published 1 February 2007. Potential conflicts of interest: none reported. Presented in part: Molecular Approaches to Malaria , Lorne , Australia , 1-5 February 2004. Financial support: This study was supported in part by the European Union BioMalPar Network of Excellence. B.C.U. holds a Wellcome Trust Senior Research Fellowship (079082), and T.N.W. holds a Wellcome Trust Senior Clinical Fellowship (076934/2/05/2). S.K. and K.M. are funded by the Wellcome Trust. U.K. ac- knowledges support from the European Commission, the Alexander von Humboldt Foundation, and Brunel University. This study is published with the permission of the director of the Kenya Medical Research Institute. and Tropical Medicine, Nuffield Dept. of Clinical Medicine, University of Oxford, Churchill Hospital , Old Rd., Oxford, OX3 7LJ , UK 3 Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital 4 Wellcome Trust Research Laboratories/Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast , Kilifi , Kenya Background. Macrophage-migration inhibitory factor (MIF), one of the first cytokines described, has a broad range of proinflammatory properties. The genome sequencing project of Plasmodium falciparum identified a parasite homologue of MIF. The protein is expressed during the asexual blood stages of the parasite life cycle that cause malarial disease. The identification of a parasite homologue of MIF raised the question of whether it affects monocyte function in a manner similar to its human counterpart. Methods. Recombinant P. falciparum MIF (PfMIF) was generated and used in vitro to assess its influence on monocyte function. Antibodies generated against PfMIF were used to determine the expression profile and localization of the protein in blood-stage parasites. Antibody responses to PfMIF were determined in Kenyan children with acute malaria and in control subjects. Results. PfMIF protein was expressed in asexual blood-stage parasites, localized to the Maurer's cleft. In vitro treatment of monocytes with PfMIF inhibited random migration and reduced the surface expression of Toll-like receptor (TLR) 2, TLR4, and CD86. Conclusions. These results indicate that PfMIF is released during blood-stage malaria and potentially modulates the function of monocytes during acute P. falciparum infection. More than 40% of the world's population is currently at risk of exposure to malaria, and an estimated 1.5-3 million deaths are attributed to Plasmodium infection per year [1, 2]. A majority of malaria cases occur in sub-Saharan Africa, with most deaths occurring in children !5 years of age. P. falciparum infection, especially - severe malaria, is known to be associated with an acute inflammatory response. This is characterized by elevated levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)a, interferon-g, and interleukin (IL)6 [3]. This inflammatory response may lead to an increase in the cytoadherence of infected red blood cells (iRBCs) to vascular endothelium, resulting in more-severe malarial disease [4]. A putative protein identified during the sequencing of the P. falciparum genome showed sequence homology to the proinflammatory cytokine macrophage-migration inhibitory factor (MIF) [5]. Microarray studies have suggested that P. falciparum MIF (PfMIF) mRNA is transcribed in late ring and early trophozoite stages of the asexual blood cycle of the parasite [6]. The identification of a MIF homologue in P. falciparum suggested a potential mechanism that might contribute to the proinflammatory cytokine profile observed during infection. Human MIF (huMIF) was one of the first cytokines identified and has a wide range of biological activities, including the induction of TNF-a, nitric oxide, IL-6, and IL-8 secretion; the up-regulation of Toll-like receptor (TLR) 4 and intercellular adhesion molecule (ICAM) 1 expression; and the suppression of the effects of glucocorticoids [7, 8]. MIF has been directly implicated in a wide range of infectious and immune-mediated diseases, including sepsis, rheumatoid arthritis, and diabetes [7]. Interestingly, homologues of MIF have been identified in filarial nematodes and in one tick species and show remarkable similarity to mammalian MIF in both crystal structure and in vitro biological activity [9, 10]. These homologues are thought to play an important role in parasite immune-evasion strategies. The role played by Pf (...truncated)


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Damien V. Cordery, Uday Kishore, Sue Kyes, Mohammed J. Shafi, Katherine R. Watkins, Thomas N. Williams, Kevin Marsh, Britta C. Urban. Characterization of a Plasmodium falciparum Macrophage-Migration Inhibitory Factor Homologue, Journal of Infectious Diseases, 2007, pp. 905-912, 195/6, DOI: 10.1086/511309