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    Circulating macrophage migration inhibitory factor (MIF) and peripheral blood mononuclear cell (PBMC) MIF mRNA in healthy children with prior mild malaria or prior severe malaria. Children were stratified into prior mild malaria (PMM, n = 15) and prior severe malaria (PSM, n = 10) based on their history of malaria disease severity. A, Plasma levels of MIF are presented as box plots where the box represents the interquartile range, the line through the box is the median, whiskers indicate the 10th and 90th percentiles, and individual symbols are outliers. *Differences in MIF levels in PMM compared with PSM were statistically significant (P < 0.005, by Mann-Whitney U test). B, Mean ± SEM MIF mRNA levels relative to β-actin mRNA for the two groups. MIF mRNA levels in PSM (n = 12) compared with PMM (n = 8) were not statistically significant (P = 0.2, by Student’s t-test). There was insufficient RNA obtained from PBMCs of five children and as such their samples failed to amplify during the reverse transcription–polymerase chain reaction.

  • 1

    Guilbert JJ, 2003. The world health report 2002—reducing risks, promoting healthy life. Educ Health (Abingdon) 16 :230.

  • 2

    World Health Organization, 2000. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–90.

    • Search Google Scholar
    • Export Citation
  • 3

    Taylor T, Olola C, Valim C, Agbenyega T, Kremsner P, Krishna S, Kwiatkowski D, Newton C, Missinou M, Pinder M, Wypij D, 2006. Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the SMAC network. Trans R Soc Trop Med Hyg 100 :615–622.

    • Search Google Scholar
    • Export Citation
  • 4

    Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO, Palmer A, Weber MW, Pinder M, Nahlen B, Obonyo C, Newbold C, Gupta S, Marsh K, 1997. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 349 :1650–1654.

    • Search Google Scholar
    • Export Citation
  • 5

    Kwiatkowski DP, 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77 :171–192.

    • Search Google Scholar
    • Export Citation
  • 6

    Clark IA, Alleva LM, Mills AC, Cowden WB, 2004. Pathogenesis of malaria and clinically similar conditions. Clin Microbiol Rev 17 :509–539.

    • Search Google Scholar
    • Export Citation
  • 7

    Clark IA, Cowden WB, 2003. The pathophysiology of falciparum malaria. Pharmacol Ther 99 :221–260.

  • 8

    Awandare GA, Hittner JB, Kremsner PG, Ochiel DO, Keller CC, Weinberg JB, Clark IA, Perkins DJ, 2006. Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria. Clin Immunol 119 :219–225.

    • Search Google Scholar
    • Export Citation
  • 9

    Awandare GA, Ouma C, Keller CC, Were T, Otieno R, Ouma Y, Davenport GC, Hittner JB, Ong’echa JM, Ferrell R, Perkins DJ, 2006. A macrophage migration inhibitory factor promoter polymorphism is associated with high-density parasitemia in children with malaria. Genes Immun 7 :568–575.

    • Search Google Scholar
    • Export Citation
  • 10

    Awandare GA, Ouma Y, Ouma C, Were T, Otieno R, Keller CC, Davenport GC, Hittner JB, Vulule J, Ferrell R, Ong’echa JM, Perkins DJ, 2007. Role of monocyte-acquired hemozoin in suppression of macrophage migration inhibitory factor in children with severe malarial anemia. Infect Immun 75 :201–210.

    • Search Google Scholar
    • Export Citation
  • 11

    Calandra T, Spiegel LA, Metz CN, Bucala R, 1998. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci U S A 95 :11383–11388.

    • Search Google Scholar
    • Export Citation
  • 12

    Koebernick H, Grode L, David JR, Rohde W, Rolph MS, Mittrucker HW, Kaufmann SH, 2002. Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium.Proc Natl Acad Sci U S A 99 :13681– 13686.

    • Search Google Scholar
    • Export Citation
  • 13

    Juttner S, Bernhagen J, Metz CN, Rollinghoff M, Bucala R, Gessner A, 1998. Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha. J Immunol 161 :2383–2390.

    • Search Google Scholar
    • Export Citation
  • 14

    Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R, 1993. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365 :756–759.

    • Search Google Scholar
    • Export Citation
  • 15

    Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, Heumann D, Mannel D, Bucala R, Glauser MP, 2000. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6 :164–170.

    • Search Google Scholar
    • Export Citation
  • 16

    Reyes JL, Terrazas LI, Espinoza B, Cruz-Robles D, Soto V, Rivera-Montoya I, Gomez-Garcia L, Snider H, Satoskar AR, Rodriguez-Sosa M, 2006. Macrophage migration inhibitory factor contributes to host defense against acute Trypanosoma cruzi infection. Infect Immun 74 :3170–3179.

    • Search Google Scholar
    • Export Citation
  • 17

    Calandra T, Roger T, 2003. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3 :791–800.

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    Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R, 1996. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A 93 :7849–7854.

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    • Export Citation
  • 19

    Chaisavaneeyakorn S, Moore JM, Othoro C, Otieno J, Chaiyaroj SC, Shi YP, Nahlen BL, Lal AA, Udhayakumar V, 2002. Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis 186 :1371–1375.

    • Search Google Scholar
    • Export Citation
  • 20

    Chaiyaroj SC, Rutta AS, Muenthaisong K, Watkins P, Na Ubol M, Looareesuwan S, 2004. Reduced levels of transforming growth factor-beta1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria. Acta Trop 89 :319–327.

    • Search Google Scholar
    • Export Citation
  • 21

    Martiney JA, Sherry B, Metz CN, Espinoza M, Ferrer AS, Calandra T, Broxmeyer HE, Bucala R, 2000. Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: possible role in the pathogenesis of malarial anemia. Infect Immun 68 :2259–2267.

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    • Export Citation
  • 22

    McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R, 2006. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203 :1185–1196.

    • Search Google Scholar
    • Export Citation
  • 23

    Perkins DJ, Kremsner PG, Schmid D, Misukonis MA, Kelly MA, Weinberg JB, 1999. Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy Gabonese children with prior mild or severe malaria. Infect Immun 67 :4977–4981.

    • Search Google Scholar
    • Export Citation
  • 24

    Kun JF, Schmidt-Ott RJ, Lehman LG, Lell B, Luckner D, Greve B, Matousek P, Kremsner PG, 1998. Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambarènè, Gabon. Trans R Soc Trop Med Hyg 92 :110–114.

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    Luty AJ, Perkins DJ, Lell B, Schmidt-Ott R, Lehman LG, Luckner D, Greve B, Matousek P, Herbich K, Schmid D, Weinberg JB, Kremsner PG, 2000. Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect Immun 68 :3909–3915.

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    Donn R, Alourfi Z, De Benedetti F, Meazza C, Zeggini E, Lunt M, Stevens A, Shelley E, Lamb R, Ollier WE, Thomson W, Ray D, 2002. Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 46 :2402–2409.

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    Donn R, Alourfi Z, Zeggini E, Lamb R, Jury F, Lunt M, Meazza C, De Benedetti F, Thomson W, Ray D, 2004. A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 50 :1604–1610.

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    Baugh JA, Chitnis S, Donnelly SC, Monteiro J, Lin X, Plant BJ, Wolfe F, Gregersen PK, Bucala R, 2002. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3 :170–176.

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HIGHER PRODUCTION OF PERIPHERAL BLOOD MACROPHAGE MIGRATION INHIBITORY FACTOR IN HEALTHY CHILDREN WITH A HISTORY OF MILD MALARIA RELATIVE TO CHILDREN WITH A HISTORY OF SEVERE MALARIA

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  • 1 Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Medical Research Unit, Albert Schweitzer Hospital, Lambarènè, Gabon; Department of Parasitology, Institute for Tropical Medicine, University of Tübingen, Tübingen,Germany; Department of Psychology, College of Charleston, Charleston, South Carolina; Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania; Department of Medicine, VA and Duke University Medical Centers, Durham, North Carolina; School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australia

Plasmodium falciparum malaria is one of the leading causes of childhood morbidity and mortality in sub-Saharan Africa. The host immune response to P. falciparum is a critical determinant of malarial pathogenesis and disease outcomes. Macrophage migration inhibitory factor (MIF) is a central regulator of innate immune responses to bacterial and parasitic infections. Our recent investigations demonstrated that peripheral blood MIF production was suppressed in children with severe malaria. Because examination of MIF production in children with active disease does not account for the inherent ability of the host to generate MIF, basal circulating MIF and peripheral blood mononuclear cell (PBMC) MIF transcript levels were determined in healthy children with a history of either mild or severe malaria. Children with prior mild malaria had higher plasma MIF levels and PBMC MIF transcripts than children with an identical number of previous episodes of severe malaria. These results suggest that increased basal MIF production may be important in generating immune responses that protect against the development of severe malaria.

More than one million people in sub-Saharan Africa die each year from Plasmodium falciparum malaria, with most deaths occurring in children less than five years of age.1 The clinical manifestations of pediatric P. falciparum malaria vary from asymptomatic infection to severe life-threatening complications, such as hyperparasitemia, hypoglycemia, cerebral malaria, severe anemia, respiratory distress, and hyperlactatemia.2,3 A number of important factors appear to influence disease severity, including host genetic variation, age of first exposure, and rate of exposure (endemicity).4,5 In addition, it is well established that the host immune response to P. falciparum is an important determinant of the development and outcomes of childhood malaria.6,7

As part of our ongoing studies examining the role of the host immune response in conditioning the outcomes of pediatric malaria, we have been investigating the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of malaria.810 Many studies have identified MIF as a central regulator of innate and adaptive immune responses that could mediate both protection and enhanced pathogenesis of bacterial and parasitic infections.1118 Although previous studies in placental malaria and in murine models of malaria have suggested a pathogenic role for MIF in malaria,1922 our recent studies demonstrate that increased circulating MIF production is associated with protection from severe childhood malaria.8,10

To further clarify the role of MIF in malarial immunity, we examined MIF protein levels in the circulation and MIF mRNA levels in peripheral blood mononuclear cells (PBMCs) from a group of healthy children (2–8 years of age, mean age = 6.3 years) enrolled in a longitudinal prospective study previously conducted at the Albert Schweitzer Hospital in Lambarènè, Gabon, a hyperendemic area for P. falciparum transmission. In this region, hyperparasitemia and severe anemia are the predominant complications of severe malaria.2325 Study participants selected for investigation were in the convalescent phase of malaria and were free of malaria parasites and any other detectable diseases for four or more months based on bi-monthly malaria parasitemia determinations and clinical evaluations. A more detailed description of this study cohort is provided in our previous publication.23

Based on their previous malaria disease history, children were divided into two groups: prior mild malaria (PMM, n = 15, 8 boys and 7 girls, mean age = 6 years 3 months) or prior severe malaria (PSM, n = 10, 6 boys and 4 girls, mean age = 6 years 4 months). Definitions of malaria disease severity during the acute illness were based on World Health Organization criteria,2 with severe malaria defined as > 200,000 parasites/μL and/or a hemoglobin (Hb) level ≤ 5.0g/dL and mild malaria defined as < 100,000 parasites/μL, Hb level > 5.0g/dL, and without any signs or symptoms of severe malaria. None of the study participants had a prior episode of cerebral malaria. Children in the PMM and PSM groups were matched so that the mean number of previous malaria episodes was identical in the two groups. Moreover, children selected for the PMM group had no prior history of severe malaria, and those in the PSM group had no prior history of mild malaria. Participation in the study was completely voluntary and written informed consent was obtained from the parents/ guardians of the pediatric participants. The study was reviewed and approved by the ethics committee of the International Foundation of the Albert Schweitzer Hospital, Duke University Medical Center Investigational Review Board, and the University of Pittsburgh Institutional Review Board.

Venous blood (< 5 mL) was collected into EDTA-containing vials, plasma was separated, and PBMCs were isolated according to our previous methods.26 At the time of sampling, a physical and clinical evaluation was performed to verify that the children were healthy and a thick blood smear was prepared to confirm that the study participants were free of malaria parasites. Plasma MIF concentrations were measured using a commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). The MIF transcripts were determined in ex vivo PBMCs by a Taqman® real time reverse transcription–polymerase chain reaction (Applied Biosystems, Foster City, CA) and normalized to β-actin according to our previous methods.8

Healthy children were selected for investigation because differences in MIF production during an active infection may reflect the overall response to the pathogen, and baseline measurements in disease-free children in the convalescent phase of disease likely reflects either inherent genetic differences and/or adaptation to prior malaria episodes. As shown in Figure 1, children with PMM (median = 1,704 [interquartile range = 1,161–2,497]) had significantly higher circulating MIF levels than children with PSM (1,007 [887–1,230]) (P < 0.005)]. In addition, MIF transcripts measured in ex vivo PBMC demonstrated that children with PMM had 2.4-fold higher MIF mRNA levels than children with PSM (P = 0.2, Figure 1B).

Unlike most cytokines, MIF is constitutively produced in significant quantities, and is further augmented by inflammatory stimuli.27 Therefore, baseline MIF production may be important for determining the nature and magnitude of the host immune response to an invading pathogen such as Plasmodium. Because samples examined in this study were taken from healthy children who had fully resolved their malarial infection, the observed levels of circulating MIF and PBMC MIF transcripts represent basal MIF production.

Our results show that children with prior episodes of mild malaria produce significantly higher baseline levels of MIF than children who previously experienced severe disease. Given the pivotal role of MIF in mediating innate immunity and regulation of pro-inflammatory cytokine production,12,13,16,17 we propose that elevated baseline MIF levels may protect against the development of severe malaria by promoting a rapid and potent innate immune response that could result in more efficient control over the initial phases of parasitemia. For example, adequate MIF production is required for induction of interleukin-12, tumor necrosis factor-α, and nitric oxide (NO),12,13,16 all of which are important mediators of the innate immune response to malaria.2831 In addition, because MIF is important in adaptive immunity through promotion of T cell and B cell activation and proliferation, and antibody production,18 adequate MIF concentrations may be required for an efficient antigen-specific immune response to malaria. Conversely, elevated MIF production in children with PMM may be related to the phenomenon of malarial tolerance6,7 in which increased MIF levels may provide negative-feedback mechanisms that help control over-expression of pro-inflammatory cytokines that could cause enhanced pathologic effects.

Our previous studies in the same cohort of healthy, malaria-exposed children showed that NO production was significantly higher in the PMM group.23 This finding, along with results presented here, are consistent with our hypothesis that elevated levels of regulatory inflammatory mediators in children with prior malaria exposure may condition tolerance to malaria and reduce susceptibility to severe disease.6,7 Alternatively, differences in host genetics may explain our current findings. Two polymorphisms in the MIF promoter (MIF-173 G/C and MIF-794 CAAT5-8) have been associated with functional changes in MIF production in a number of inflammatory diseases.3235 In addition, we recently demonstrated a significant association between circulating MIF levels and MIF -173 G/C variability in Kenyan children.9 Although polymorphic variability was not determined here, we are currently investigating the impact of MIF promoter polymorphisms on baseline and malaria-induced MIF production in pediatric populations.

Figure 1.
Figure 1.

Circulating macrophage migration inhibitory factor (MIF) and peripheral blood mononuclear cell (PBMC) MIF mRNA in healthy children with prior mild malaria or prior severe malaria. Children were stratified into prior mild malaria (PMM, n = 15) and prior severe malaria (PSM, n = 10) based on their history of malaria disease severity. A, Plasma levels of MIF are presented as box plots where the box represents the interquartile range, the line through the box is the median, whiskers indicate the 10th and 90th percentiles, and individual symbols are outliers. *Differences in MIF levels in PMM compared with PSM were statistically significant (P < 0.005, by Mann-Whitney U test). B, Mean ± SEM MIF mRNA levels relative to β-actin mRNA for the two groups. MIF mRNA levels in PSM (n = 12) compared with PMM (n = 8) were not statistically significant (P = 0.2, by Student’s t-test). There was insufficient RNA obtained from PBMCs of five children and as such their samples failed to amplify during the reverse transcription–polymerase chain reaction.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 76, 6; 10.4269/ajtmh.2007.76.1033

*

Address correspondence to Douglas Jay Perkins, Graduate School of Public Health, Department of Infectious Diseases and Microbiology, University of Pittsburgh, 130 DeSoto Street, 603 Parran Hall, Pittsburgh, PA 15261. E-mail: djp@pitt.edu

Authors’ addresses: Gordon A. Awandare and Douglas Jay Perkins, Graduate School of Public Health, Department of Infectious Diseases and Microbiology, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, Telephone: 412-624-5915 and 412-624-5894, Fax: 412-624-5364, E-mail: djp@pitt.edu. Peter G. Kremsner, Department of Parasitology, Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany, Telephone: 49-7071-298-7179, Fax: 49-7071- 295-189. James B. Hittner, Department of Psychology, College of Charleston 66 George Street, Charleston, SC 29424, Telephone: 843-953-6734, Fax: 843-953-7151. Christopher C. Keller, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Boulevard, Erie, PA 16509, Telephone: 814-866-8417. Ian A. Clark, School of Biochemistry and Molecular Biology, Australian National University, Canberra ACT 0200 Australia, Telephone: 61-2-6125-4363, Fax: 61-2-6125-0313. J. Brice Weinberg, Hematology-Oncology, VA and Duke University Medical Centers, 508 Fulton Street, Room E1006, Durham, NC 27705, Telephone: 919-286-6833, Fax: 919-286-6891.

Acknowledgments: Part of this work was presented at the 53rd Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH Abstract no. 775) in Miami Beach, FL (November 7–11, 2004). We thank the following staff members of Albert Schweitzer Hospital in Lambaréné Gabon for technical assistance: Dr. Anita van den Biggerlaar, Judith Jans, Dr. Hanna Knoop, Dr. Doris Luckner, Barbara Moritz, Anselme Ndzengue, Marcel Nkeyi, Dr. Daniela Schmid, and Dr. Milena Sovric. The study was conducted at the University of Pittsburgh,

Financial support: This study was supported in part by National Institutes of Health grants AI-51305-01 to Douglas Jay Perkins and AI-41764 to J. Brice Weinberg, the VA Research Service (J. Brice Weinberg) and Fogarty International Training Grant 5D43-TW00588-4 to Douglas Jay Perkins.

Disclosure: There is no conflict of interest for any of the authors of the manuscript due to either commercial or other affiliations.

REFERENCES

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    Guilbert JJ, 2003. The world health report 2002—reducing risks, promoting healthy life. Educ Health (Abingdon) 16 :230.

  • 2

    World Health Organization, 2000. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–90.

    • Search Google Scholar
    • Export Citation
  • 3

    Taylor T, Olola C, Valim C, Agbenyega T, Kremsner P, Krishna S, Kwiatkowski D, Newton C, Missinou M, Pinder M, Wypij D, 2006. Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the SMAC network. Trans R Soc Trop Med Hyg 100 :615–622.

    • Search Google Scholar
    • Export Citation
  • 4

    Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO, Palmer A, Weber MW, Pinder M, Nahlen B, Obonyo C, Newbold C, Gupta S, Marsh K, 1997. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 349 :1650–1654.

    • Search Google Scholar
    • Export Citation
  • 5

    Kwiatkowski DP, 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77 :171–192.

    • Search Google Scholar
    • Export Citation
  • 6

    Clark IA, Alleva LM, Mills AC, Cowden WB, 2004. Pathogenesis of malaria and clinically similar conditions. Clin Microbiol Rev 17 :509–539.

    • Search Google Scholar
    • Export Citation
  • 7

    Clark IA, Cowden WB, 2003. The pathophysiology of falciparum malaria. Pharmacol Ther 99 :221–260.

  • 8

    Awandare GA, Hittner JB, Kremsner PG, Ochiel DO, Keller CC, Weinberg JB, Clark IA, Perkins DJ, 2006. Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria. Clin Immunol 119 :219–225.

    • Search Google Scholar
    • Export Citation
  • 9

    Awandare GA, Ouma C, Keller CC, Were T, Otieno R, Ouma Y, Davenport GC, Hittner JB, Ong’echa JM, Ferrell R, Perkins DJ, 2006. A macrophage migration inhibitory factor promoter polymorphism is associated with high-density parasitemia in children with malaria. Genes Immun 7 :568–575.

    • Search Google Scholar
    • Export Citation
  • 10

    Awandare GA, Ouma Y, Ouma C, Were T, Otieno R, Keller CC, Davenport GC, Hittner JB, Vulule J, Ferrell R, Ong’echa JM, Perkins DJ, 2007. Role of monocyte-acquired hemozoin in suppression of macrophage migration inhibitory factor in children with severe malarial anemia. Infect Immun 75 :201–210.

    • Search Google Scholar
    • Export Citation
  • 11

    Calandra T, Spiegel LA, Metz CN, Bucala R, 1998. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci U S A 95 :11383–11388.

    • Search Google Scholar
    • Export Citation
  • 12

    Koebernick H, Grode L, David JR, Rohde W, Rolph MS, Mittrucker HW, Kaufmann SH, 2002. Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium.Proc Natl Acad Sci U S A 99 :13681– 13686.

    • Search Google Scholar
    • Export Citation
  • 13

    Juttner S, Bernhagen J, Metz CN, Rollinghoff M, Bucala R, Gessner A, 1998. Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha. J Immunol 161 :2383–2390.

    • Search Google Scholar
    • Export Citation
  • 14

    Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R, 1993. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365 :756–759.

    • Search Google Scholar
    • Export Citation
  • 15

    Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, Heumann D, Mannel D, Bucala R, Glauser MP, 2000. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6 :164–170.

    • Search Google Scholar
    • Export Citation
  • 16

    Reyes JL, Terrazas LI, Espinoza B, Cruz-Robles D, Soto V, Rivera-Montoya I, Gomez-Garcia L, Snider H, Satoskar AR, Rodriguez-Sosa M, 2006. Macrophage migration inhibitory factor contributes to host defense against acute Trypanosoma cruzi infection. Infect Immun 74 :3170–3179.

    • Search Google Scholar
    • Export Citation
  • 17

    Calandra T, Roger T, 2003. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3 :791–800.

  • 18

    Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R, 1996. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A 93 :7849–7854.

    • Search Google Scholar
    • Export Citation
  • 19

    Chaisavaneeyakorn S, Moore JM, Othoro C, Otieno J, Chaiyaroj SC, Shi YP, Nahlen BL, Lal AA, Udhayakumar V, 2002. Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis 186 :1371–1375.

    • Search Google Scholar
    • Export Citation
  • 20

    Chaiyaroj SC, Rutta AS, Muenthaisong K, Watkins P, Na Ubol M, Looareesuwan S, 2004. Reduced levels of transforming growth factor-beta1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria. Acta Trop 89 :319–327.

    • Search Google Scholar
    • Export Citation
  • 21

    Martiney JA, Sherry B, Metz CN, Espinoza M, Ferrer AS, Calandra T, Broxmeyer HE, Bucala R, 2000. Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: possible role in the pathogenesis of malarial anemia. Infect Immun 68 :2259–2267.

    • Search Google Scholar
    • Export Citation
  • 22

    McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R, 2006. A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203 :1185–1196.

    • Search Google Scholar
    • Export Citation
  • 23

    Perkins DJ, Kremsner PG, Schmid D, Misukonis MA, Kelly MA, Weinberg JB, 1999. Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy Gabonese children with prior mild or severe malaria. Infect Immun 67 :4977–4981.

    • Search Google Scholar
    • Export Citation
  • 24

    Kun JF, Schmidt-Ott RJ, Lehman LG, Lell B, Luckner D, Greve B, Matousek P, Kremsner PG, 1998. Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambarènè, Gabon. Trans R Soc Trop Med Hyg 92 :110–114.

    • Search Google Scholar
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