Abstract
The ability of nematode parasites to survive in a highly complex immune system involves diverse strategies including production of a variety of host immune modulators. Various parasite-associated surface antigens or excretory and secretory products may possibly play a role in the host–parasite interactions and successful survival of parasite in their respective host. One among these molecules is a human cytokine homolog, macrophage migration inhibitory factor-1 (MIF-1) in various parasites. We identified a homolog of this cytokine from human lymphatic filarial parasite, Wuchereria bancrofti, expression cloned and investigated its molecular characteristics and catalytic properties. We also assessed the humoral reactivity of the recombinant MIF-1 of W. bancrofti (rWb-MIF-1) against sera belonging to different categories of individuals viz. microfilaremic, chronic patients, endemic normal, and non-endemic normal. Our results showed that the complete coding sequence of W. bancrofti is 1,078 bp, comprising two introns and three exons: first and second introns being 577 and 153 bp long, while the three exons I, II, and III being 108, 173, and 67 bp long, respectively. The rWb-MIF-1 was overexpressed in a salt-inducible host, Escherichia coli GJ 1158, and its functional activity was determined by dopachrome tautomerase and insulin reduction assays. The results of both the assays showed that the purified protein is functionally active and hence folded appropriately. The rWb-MIF-1 protein did not show elevation of specific IgG4 antibodies in microfilaremic cases, a hallmark in case of lymphatic filariasis, while it showed IgE reactivity in some of these cases (five out of ten).
Similar content being viewed by others
References
Allen JE, Maizels RM (2011) Diversity and dialogue in immunity to helminths. Nat Rev Immunol 11:375–388
Allen JE, Wynn TA (2011) Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 5:e1002003
Aravindhan V, Mohan V, Surendar J, Muralidhara Rao M, Pavankumar N, Deepa M, Rajagopalan R, Kumaraswami V, Nutman TB, Babu S (2010) Decreased prevalence of lymphatic filariasis among diabetic subjects associated with a diminished pro-inflammatory cytokine response. PLoS Negl Trop Dis 4:e707
Augustijn KD, Kleemann R, Thompson J, Kooistra T, Crawford CE, Reece SE, Pain A, Siebum AH, Janse CJ, Waters AP (2007) Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor. Infect Immun 75:1116–1128
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 93:7849–7854
Baugh JA, Donnelly SC (2003) Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J Endocrinol 179:15–23
Behnke JM, Williams DJ, Hannah J, Pritchard DI (1987) Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius): the capacity of adult worms to survive following transplantation to recipient mice. Parasitology 95:569–581
Bennuru S, Meng Z, José MC, Ribeiro RT, Semnani EG, Chan K, Lucas DA, Veenstra TD, Nutman TB (2011) Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia. PNAS 108:9649–9654
Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 10:791–800
Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hültner L, Heumann D, Männel D, Bucala R, Glauser MP (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164–170
Cass CL, Johnson JR, Califf LL, Xub T, Hernandez HJ, Stadecker MJ, Yates JR, Williams DL (2007) Proteomic analysis of Schistosoma mansoni egg secretions. Mol Biochem Parasitol 155:84–93
Chandrasekhar R, Rao UR, Rajasekariah GR, Subramanyam D (1984) Isolation of microfilariae from blood on iso-osmotic percoll gradient. Indian J Med Res 79:497–501
Cho Y, Jones BF, Vermeire JJ, Leng L, DiFedele L, Harrison LM, Xiong H, Kwong YK, Chen Y, Bucala R, Lolis E, Cappello M (2007) Structural and functional characterization of a secreted hookworm macrophage migration inhibitory factor (MIF) that interacts with the human MIF receptor CD74. J Biol Chem 282:23447–23456
Cho Y, Vermeire JJ, Merkel JS, Leng L, Du X, Bucala R, Cappello M, Lolis E (2011) Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors. Chem Biol 18:1089–1101
Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y (2007) Alternative chemical modifications reverse the binding orientation of apharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol Chem 282:23089–23095
Dabideen DR, Cheng KF, Aljabari B, Miller EJ, Pavlov VA, Al-Abed Y (2007) Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis. J Med Chem 50:1993–1997
Díaz A, Allen JE (2007) Mapping immune response profiles: the emerging scenario from helminth immunology. Eur J Immunol 37:3319–3326
Dios A, Mitchell RA, Aljabari B, Lubetsky J, O'Connor K, Liao H, Senter PD, Manogue KR, Lolis E, Metz C, Bucala R, Callaway DJ, Al-Abed Y (2002) Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity. J Med Chem 12:2410–2416
Donn R, Alourfi Z, Zeggini E, Lamb R, Jury F, Lunt M, Meazza C, De Benedetti F, Thomson W, Ray D, British Paediatric Rheumatology Study Group (2004) A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 50:1604–1610
Donnelly SC, Bucala R (1997) Macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease. Mol Med Today 3:502–507
Ellis LB, Saurugger P, Woodward C (1992) Identification of the three-dimensional thioredoxin motif: related structure in the ORF3 protein of the Staphylococcus aureus mer operon. Biochemistry 31(20):4882–4891
Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127:514–525
Enoksson M, Lyberg K, Möller-Westerberg C, Fallon PG, Nilsson G, Lunderius-Andersson C (2011) Mast cells as sensors of cell injury through IL-33 recognition. J Immunol 186:2523–2528
Falcone FH, Loke P, Zang X, MacDonald AS, Maizels RM, Allen JE (2001) A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection. J Immunol 167:5348–5354
Fallon PG, Alcami A (2006) Pathogen-derived immunomodulatory molecules: future immunotherapeutics? Trends Immunol 27:470–476
Finkelman FD, Shea-Donohue T, Morris SC, Gildea L, Strait R, Madden KB, Schopf L, Urban JF Jr (2004) Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol Rev 201:139–155
Gregory WF, Maizels RM (2008) Cystatins from filarial parasites: evolution, adaptation and function in the host-parasite relationship. Int J Biochem Cell Biol 40:1389–1398
Han ZF, Shao DD, Wang H (2004) Cloning and expression of a homologue of human macrophage migration inhibitory factor from P. falciparum 3D7. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 26:515–518
Harnett MM, Harnett W (2001) Antigen receptor signaling is subverted by an immunomodulatory product secreted by a filarial nematode. Arch Immunol Ther 49:263–269
Harnett W, McInnis IB, Harnett MM (2004) ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential. Immunol Lett 15:27–33
Hartmann S, Lucius R (2003) Modulation of host immune responses by nematode cystatins. Int J Parasitol 33:1291–1302
Holmgren A (1979) Thioredoxin catalyzes the reduction of insulin disulfides by dithiothreitol and dihydrolipoamide. J Biol Chem 254:9627–9632
James SL, Glaven J (1989) Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J Immunol 143:4208–4212
Kleemann R, Kapurniotu A, Frank RW, Gessner A, Mischke R, Flieger O, Jüttner S, Brunner H, Bernhagen J (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 280:85–102
Kleemann R, Kapurniotu A, Mischke R, Held J, Bernhagen J (1999) Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81 Ser MIF. Eur J Biochem 261(3):753–766
Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J (2000) Intracellular action of the cytokine MIF to modulate AP-1activity and the cell cycle through Jab1. Nature 408:211–216
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685
Lowry OH, Rosebrough NJ, Farr AL, Randall RI (1951) Protein measurement with the Folin phenol reagent. JBiol Chem 193:265–275
Lubetsky JB, Swope M, Dealwis C, Blake P, Lolis E (1999) Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity. Biochemistry 38:7346–7354
Maizels RM, Blaxter ML, Selkirk ME (1993) Forms and functions of nematode surfaces. Exp Parasitol 77:380–384
Maizels RM, Blaxter ML, Scott AL (2001) Immunological genomics of Brugia malayi: filarial genes implicated in immune evasion and protective immunity. Parasite Immunol 23:327–344
Metz CN, Bucala R (1997) Role of macrophage migration inhibitory factor in the regulation of the immune response. Adv Immunol 66:197–223
Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464:1367–1370
Niino M, Ogata A, Kikuchi S, Tashiro K, Nishihira J (2000) Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behçet's disease. J Neurol Sci 179:127–131
Ottesen EA (1988) Filariasis now. AmJTrop Med Hyg 41:9–17
Ottesen EA, Weller PF, Lunde MN, Hussain R (1982) Endemic filariasis on a Pacific Island. II. Immunologic aspects: immunoglobulin, complement, and specific antifilarial IgG, IgM, and IgE antibodies. AmJTrop Med Hyg 31:953–961
Pastrana DV, Raghavan N, FitzGerald P, Eisinger SW, Metz C, Bucala R, Schleimer RP, Bickel C, Scott AL (1998) Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect Immune 66:5955–5963
Platts-Mills TA, Woodfolk JA, Erwin EA, Aalberse R (2004) Mechanisms of tolerance to inhalant allergens: the relevance of a modified TH2 response to allergens from domestic animals. Springer Semin Immunopathol 25:271–279
Prieto-Lafuente L, Gregory WF, Allen JE, Maizels RM (2009) MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages. J Leukoc Biol 85:844–854
Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H (1996) The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med 2:143–149
Sasa M (1976) Human filariasis—a global survey of epidemiology and control. University of Tokyo Press, Tokyo, p 334
Sasa M, Shirasaka R, Joesoef A, Abdulwahas R, Yamaura H (1976) A study of the microfilarial periodicity at Bireuen, the type locality of Brugia malayi. Southeast Asian J Trop Med Public Health 7:370–376
Schabussova I, Amer H, van Die I, Kosma P, Maizels RM (2007) O-Methylated glycans from Toxocara are specific targets for antibody binding in human and animal infections. Int J Parasitol 37:97–109
Swope M, Sun HW, Blake PR, Lolis E (1998) Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. EMBO J 17:3534–3541
Taylor MJ, Bilo K, Cross HF, Archer JP, Underwood AP (1999) 16S rDNA phylogeny and ultrastructural characterization of Wolbachia intracellular bacteria of the filarial nematodes Brugia malayi, B. pahangi, and Wuchereria bancrofti. Exp Parasitol 91:356–361
Varatharajalu R, Parandaman V, Ndao M, Andersen JF, Neva FA (2011) Strongyloides stercoralis excretory/secretory protein strongylastacin specifically recognized by IgE antibodies in infected human sera. Microbiol Immunol 55:115–122
Vermeire JJ, Cho Y, Lolis E, Bucala R, Cappello M (2008) Orthologs of macrophage migration inhibitory factor from parasitic nematodes. Trends Parasitol 24:355–363
Verschuren L, Kooistra T, Bernhagen J, Voshol PJ, Ouwens DM, van Erk M, de Vries-van der Weij J, Leng L, van Bockel JH, van Dijk KW, Fingerle-Rowson G, Bucala R, Kleemann R (2009) MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease. Circ Res 105(1):99–107
Waeber G, Gomez F, Chaubert P, Temler E, Chapuis G, Boulat O, Nicod P, Haefliger JA (1997) In vivo and in vitro effects of somatostatin and insulin on glucagon release in a human glucagonoma. Clin Endocrinol 46:637–642
Yabunaka N, Nishihira J, Mizue Y, Tsuji M, Kumagai M, Ohtsuka Y, Imamura M, Asaka M (2000) Elevated serum content of macrophage migration inhibitory factor in patients with type 2 diabetes. Diabetes Care 23:256–258
Zang X, Taylor P, Wang JM, Meyer DJ, Scott AL, Walkinshaw MD, Maizels RM (2002) Homologues of human macrophage migration inhibitory factor from a parasitic nematode. Gene cloning, protein activity and crystal structure. J Biol Chem 15:44261–44267
Acknowledgments
Authors are thankful to Dr. P. Jambulingam, Director, for his continuous support in the preparation of the manuscript. This work was supported by Grants from Indian Council of Medical Research, New Delhi. One of the authors (RS) is the recipient of senior research fellowship from the grant.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sharma, R., Hoti, S.L., Meena, R.L. et al. Molecular and functional characterization of macrophage migration inhibitory factor (MIF) homolog of human from lymphatic filarial parasite Wuchereria bancrofti . Parasitol Res 111, 2035–2047 (2012). https://doi.org/10.1007/s00436-012-3051-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-012-3051-2