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Genetic analysis in mice identifies cysteamine as a novel partner for artemisinin in the treatment of malaria

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Abstract

Malaria continues to be a serious threat to global health. The malaria problem is compounded by the absence of an efficacious vaccine and widespread drug resistance in the Plasmodium malarial parasite. The host factors and parasite virulence determinants that regulate early response to infection and subsequent onset of protective immunity are poorly understood. The molecular characterization of this early host:pathogen interface may identify novel targets for prophylactic or therapeutic intervention. Genetic analyses in mouse model of malaria show that inactivation of the enzyme pantetheinase (Char9 locus) causes susceptibility to blood-stage infection. The pantetheinase product cysteamine is an inexpensive and non-toxic aminothiol that is approved for lifelong clinical management of nephropathic cystinosis. In mouse models of infection, cysteamine not only displays anti-malarial activity of its own, but also dramatically potentiates the anti-malarial activity of artemisinin, at doses currently used for the clinical management of cystinosis. Therefore, the inclusion of cysteamine in current artemisinin combination therapies may significantly increase efficacy and may also prove effective against emerging artemisinin-resistant human Plasmodium parasite.

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References

  • Allison AC (1954) Protection afforded by sickle-cell trait against subtertian malarial infection. Br Med J 1(4857):290–294

    Article  PubMed  CAS  Google Scholar 

  • Allison AC (2009) Genetic control of resistance to human malaria. Curr Opin Immunol 21:499–505

    Article  PubMed  CAS  Google Scholar 

  • Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818

    Article  PubMed  CAS  Google Scholar 

  • Asawamahasakda W, Ittarat I, Pu YM, Ziffer H, Meshnick SR (1994) Reaction of antimalarial endoperoxides with specific parasite proteins. Antimicrob Agents Chemother 38:1854–1858

    PubMed  CAS  Google Scholar 

  • Ayi K, Min-Oo G, Serghides L, Crockett M, Kirby-Allen M et al (2008) Pyruvate kinase deficiency and malaria. N Engl J Med 358:1805–1810

    Article  PubMed  CAS  Google Scholar 

  • Ayi K, Liles WC, Gros P, Kain KC (2009) Adenosine triphosphate depletion of erythrocytes simulates the phenotype associated with pyruvate kinase deficiency and confers protection against Plasmodium falciparum in vitro. J Infect Dis 200:1289–1299

    Article  PubMed  CAS  Google Scholar 

  • Berruyer C, Martin FM, Castellano R, Macone A, Malergue F et al (2004) Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress. Mol Cell Biol 24:7214–7224

    Article  PubMed  CAS  Google Scholar 

  • Bongfen SE, Laroque A, Berghout J, Gros P (2009) Genetic and genomic analyses of host-pathogen interactions in malaria. Trends Parasitol 25:417–422

    Article  PubMed  CAS  Google Scholar 

  • Borrell-Pages M, Canals JM, Cordelieres FP, Parker JA, Pineda JR et al (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116:1410–1424

    Article  PubMed  CAS  Google Scholar 

  • Bousquet M, Gibrat C, Ouellet M, Rouillard C, Calon F et al (2010) Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases. J Neurochem 114:1651–1658

    Article  PubMed  CAS  Google Scholar 

  • Brooke BD, Koekemoer LL (2010) Major effect genes or loose confederations? The development of insecticide resistance in the malaria vector Anopheles gambiae. Parasit Vectors 3:74

    Article  PubMed  Google Scholar 

  • Chavchich M, Gerena L, Peters J, Chen N, Cheng Q et al (2010) Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrob Agents Chemother 54:2455–2464

    Article  PubMed  CAS  Google Scholar 

  • Di Leandro L, Maras B, Schinina ME, Dupre S, Koutris I et al (2008) Cystamine restores GSTA3 levels in Vanin-1 null mice. Free Radic Biol Med 44:1088–1096

    Article  PubMed  CAS  Google Scholar 

  • Dohil R, Fidler M, Gangoiti JA, Kaskel F, Schneider JA et al (2010) Twice-daily cysteamine bitartrate therapy for children with cystinosis. J Pediatr 156:71–75

    Article  PubMed  CAS  Google Scholar 

  • Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005) Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366:717–725

    Article  PubMed  Google Scholar 

  • Dondorp AM, Nosten F, Yi P, Das D, Phyo AP et al (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467

    Article  PubMed  CAS  Google Scholar 

  • Dondorp AM, Yeung S, White L, Nguon C, Day NP et al (2010) Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 8:272–280

    Article  PubMed  CAS  Google Scholar 

  • Dunay IR, Chan WC, Haynes RK, Sibley LD (2009) Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother 53:4450–4456

    Article  PubMed  CAS  Google Scholar 

  • Dupre S, Granata F, Santoro L, Scandurra R, Federici G et al (1975) In vitro enzymatic conversion of pantothenylcysteine-4′-phosphate into cysteamine. Ital J Biochem 24:269–276

    PubMed  CAS  Google Scholar 

  • Eastman RT, Fidock DA (2009) Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nat Rev Microbiol 7:864–874

    PubMed  CAS  Google Scholar 

  • Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG et al (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424:957–961

    Article  PubMed  CAS  Google Scholar 

  • Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJ et al (2008) The antiviral activities of artemisinin and artesunate. Clin Infect Dis 47:804–811

    Article  PubMed  CAS  Google Scholar 

  • Fidler MC, Barshop BA, Gangoiti JA, Deutsch R, Martin M et al (2007) Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Br J Clin Pharmacol 63:36–40

    Article  PubMed  CAS  Google Scholar 

  • Firestone GL, Sundar SN (2009) Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 11:e32

    Article  PubMed  Google Scholar 

  • Frankish H (2006) Drug shows potential for treatment of Huntington’s disease. Lancet Neurol 5:476–477

    Article  PubMed  Google Scholar 

  • Gangoiti JA, Fidler M, Cabrera BL, Schneider JA, Barshop BA et al (2010) Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study. Br J Clin Pharmacol 70:376–382

    Article  PubMed  CAS  Google Scholar 

  • Genton B, al-Yaman F, Mgone CS, Alexander N, Paniu MM et al (1995) Ovalocytosis and cerebral malaria. Nature 378:564–565

    Article  PubMed  CAS  Google Scholar 

  • Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL et al (2008) Malaria: progress, perils, and prospects for eradication. J Clin Invest 118:1266–1276

    Article  PubMed  CAS  Google Scholar 

  • Hernandez-Valladares M, Naessens J, Iraqi FA (2005) Genetic resistance to malaria in mouse models. Trends Parasitol 21:352–355

    Article  PubMed  CAS  Google Scholar 

  • Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P et al (2009) Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet 41:657–665

    Article  PubMed  CAS  Google Scholar 

  • Jin O, Zhang H, Gu Z, Zhao S, Xu T et al (2009) A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus. Cell Mol Immunol 6:461–467

    Article  PubMed  CAS  Google Scholar 

  • Kalatzis V, Cherqui S, Antignac C, Gasnier B (2001) Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. EMBO J 20:5940–5949

    Article  PubMed  CAS  Google Scholar 

  • Kamchonwongpaisan S, Meshnick SR (1996) The mode of action of the antimalarial artemisinin and its derivatives. Gen Pharmacol 27:587–592

    PubMed  CAS  Google Scholar 

  • Kappe SH, Vaughan AM, Boddey JA, Cowman AF (2010) That was then but this is now: malaria research in the time of an eradication agenda. Science 328:862–866

    Article  PubMed  CAS  Google Scholar 

  • Keiser J, Utzinger J (2007) Artemisinins and synthetic trioxolanes in the treatment of helminth infections. Curr Opin Infect Dis 20:605–612

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lamb TJ, Brown DE, Potocnik AJ, Langhorne J (2006) Insights into the immunopathogenesis of malaria using mouse models. Expert Rev Mol Med 8:1–22

    Article  PubMed  Google Scholar 

  • Lawaly YR, Sakuntabhai A, Marrama L, Konate L, Phimpraphi W et al (2010) Heritability of the human infectious reservoir of malaria parasites. PLoS One 5:e11358

    Article  PubMed  Google Scholar 

  • Louicharoen C, Patin E, Paul R, Nuchprayoon I, Witoonpanich B et al (2009) Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians. Science 326:1546–1549

    Article  PubMed  CAS  Google Scholar 

  • Luersen K, Walter RD, Muller S (2000) Plasmodium falciparum-infected red blood cells depend on a functional glutathione de novo synthesis attributable to an enhanced loss of glutathione. Biochem J 346(Pt 2):545–552

    Article  PubMed  CAS  Google Scholar 

  • Maier AG, Duraisingh MT, Reeder JC, Patel SS, Kazura JW et al (2003) Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nat Med 9:87–92

    Article  PubMed  CAS  Google Scholar 

  • Martin F, Malergue F, Pitari G, Philippe JM, Philips S et al (2001) Vanin genes are clustered (human 6q22–24 and mouse 10A2B1) and encode isoforms of pantetheinase ectoenzymes. Immunogenetics 53:296–306

    Article  PubMed  CAS  Google Scholar 

  • Martin F, Penet MF, Malergue F, Lepidi H, Dessein A et al (2004) Vanin-1(-/-) mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores. J Clin Invest 113:591–597

    PubMed  CAS  Google Scholar 

  • Martinelli A, Rodrigues LA, Cravo P (2008) Plasmodium chabaudi: efficacy of artemisinin + curcumin combination treatment on a clone selected for artemisinin resistance in mice. Exp Parasitol 119:304–307

    Article  PubMed  CAS  Google Scholar 

  • Matuschewski K (2006) Getting infectious: formation and maturation of Plasmodium sporozoites in the Anopheles vector. Cell Microbiol 8:1547–1556

    Article  PubMed  CAS  Google Scholar 

  • McDowell GA, Town MM, van’t Hoff W, Gahl WA (1998) Clinical and molecular aspects of nephropathic cystinosis. J Mol Med 76:295–302

    Article  PubMed  CAS  Google Scholar 

  • McIntosh HM, Olliaro P (2000) Artemisinin derivatives for treating uncomplicated malaria. Cochrane Database Syst Rev (2):CD000256

  • Meshnick SR (2002) Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 32:1655–1660

    Article  PubMed  CAS  Google Scholar 

  • Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S et al (1993) Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrob Agents Chemother 37:1108–1114

    PubMed  CAS  Google Scholar 

  • Meshnick SR, Taylor TE, Kamchonwongpaisan S (1996) Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 60:301–315

    PubMed  CAS  Google Scholar 

  • Miller LH, Mason SJ, Clyde DF, McGinniss MH (1976) The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med 295:302–304

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Gros P (2005) Erythrocyte variants and the nature of their malaria protective effect. Cell Microbiol 7:753–763

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Fortin A, Tam MF, Nantel A, Stevenson MM et al (2003) Pyruvate kinase deficiency in mice protects against malaria. Nat Genet 35:357–362

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Fortin A, Pitari G, Tam M, Stevenson MM et al (2007a) Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus. J Exp Med 204:511–524

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Tam M, Stevenson MM, Gros P (2007b) Pyruvate kinase deficiency: correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants. Blood Cells Mol Dis 39:63–69

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Ayi K, Bongfen SE, Tam M, Radovanovic I et al (2010a) Cysteamine, the natural metabolite of pantetheinase, shows specific activity against Plasmodium. Exp Parasitol 125:315–324

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Fortin A, Poulin JF, Gros P (2010b) Cysteamine, the molecule used to treat cystinosis, potentiates the antimalarial efficacy of artemisinin. Antimicrob Agents Chemother 54:3262–3270

    Article  PubMed  CAS  Google Scholar 

  • Min-Oo G, Willemetz A, Tam M, Canonne-Hergaux F, Stevenson MM et al (2010c) Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9. Genes Immun 11:113–123

    Article  PubMed  CAS  Google Scholar 

  • Mishra SK, Wiese L (2009) Advances in the management of cerebral malaria in adults. Curr Opin Neurol 22:302–307

    Article  PubMed  Google Scholar 

  • Mita T, Tanabe K, Kita K (2009) Spread and evolution of Plasmodium falciparum drug resistance. Parasitol Int 58:201–209

    Article  PubMed  CAS  Google Scholar 

  • Mockenhaupt FP, Ehrhardt S, Gellert S, Otchwemah RN, Dietz E et al (2004) Alpha(+)-thalassemia protects African children from severe malaria. Blood 104:2003–2006

    Article  PubMed  CAS  Google Scholar 

  • Modiano D, Luoni G, Sirima BS, Simpore J, Verra F et al (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414:305–308

    Article  PubMed  CAS  Google Scholar 

  • Nandakumar DN, Nagaraj VA, Vathsala PG, Rangarajan P, Padmanaban G (2006) Curcumin-artemisinin combination therapy for malaria. Antimicrob Agents Chemother 50:1859–1860

    Article  PubMed  CAS  Google Scholar 

  • Nesterova G, Gahl W (2008) Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol 23:863–878

    Article  PubMed  Google Scholar 

  • Noedl H, Se Y, Schaecher K, Smith BL, Socheat D et al (2008) Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359:2619–2620

    Article  PubMed  CAS  Google Scholar 

  • Noedl H, Socheat D, Satimai W (2009) Artemisinin-resistant malaria in Asia. N Engl J Med 361:540–541

    Article  PubMed  CAS  Google Scholar 

  • Nosten F, White NJ (2007) Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 77:181–192

    PubMed  CAS  Google Scholar 

  • Olivieri NF, Muraca GM, O’Donnell A, Premawardhena A, Fisher C et al (2008) Studies in haemoglobin E beta-thalassaemia. Br J Haematol 141:388–397

    Article  PubMed  CAS  Google Scholar 

  • Palmer KJ, Holliday SM, Brogden RN (1993) Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 45:430–475

    Article  PubMed  CAS  Google Scholar 

  • Patel SN, Kain KC (2005) Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev Anti Infect Ther 3:849–861

    Article  PubMed  CAS  Google Scholar 

  • Pinto JT, Van Raamsdonk JM, Leavitt BR, Hayden MR, Jeitner TM et al (2005) Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: implications for the treatment of Huntington disease. J Neurochem 94:1087–1101

    Article  PubMed  CAS  Google Scholar 

  • Pitari G, Malergue F, Martin F, Philippe JM, Massucci MT et al (2000) Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice. FEBS Lett 483:149–154

    Article  PubMed  Google Scholar 

  • Ploypradith P (2004) Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs. Acta Trop 89:329–342

    Article  PubMed  CAS  Google Scholar 

  • Pouyet L, Roisin-Bouffay C, Clement A, Millet V, Garcia S et al (2010) Epithelial vanin-1 controls inflammation-driven carcinogenesis in the colitis-associated colon cancer model. Inflamm Bowel Dis 16:96–104

    PubMed  Google Scholar 

  • Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E et al (2004) Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438–447

    Article  PubMed  CAS  Google Scholar 

  • Reddy RC, Vatsala PG, Keshamouni VG, Padmanaban G, Rangarajan PN (2005) Curcumin for malaria therapy. Biochem Biophys Res Commun 326:472–474

    Article  PubMed  CAS  Google Scholar 

  • Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL et al (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal PJ (2004) Cysteine proteases of malaria parasites. Int J Parasitol 34:1489–1499

    Article  PubMed  CAS  Google Scholar 

  • Schofield L, Grau GE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5:722–735

    Article  PubMed  CAS  Google Scholar 

  • Scholl PF, Tripathi AK, Sullivan DJ (2005) Bioavailable iron and heme metabolism in Plasmodium falciparum. Curr Top Microbiol Immunol 295:293–324

    Article  PubMed  CAS  Google Scholar 

  • Sibley CH, Hyde JE, Sims PF, Plowe CV, Kublin JG et al (2001) Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17:582–588

    Article  PubMed  CAS  Google Scholar 

  • Sinclair D, Zani B, Donegan S, Olliaro P, Garner P (2009) Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev (3):CD007483

  • Sissoko MS, Dabo A, Traore H, Diallo M, Traore B et al (2009) Efficacy of artesunate + sulfamethoxypyrazine/pyrimethamine versus praziquantel in the treatment of Schistosoma haematobium in children. PLoS One 4:e6732

    Article  PubMed  Google Scholar 

  • Slater AF, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169

    Article  PubMed  CAS  Google Scholar 

  • Timmann C, Evans JA, Konig IR, Kleensang A, Ruschendorf F et al (2007) Genome-wide linkage analysis of malaria infection intensity and mild disease. PLoS Genet 3:e48

    Article  PubMed  Google Scholar 

  • Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FC et al (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430:900–904

    Article  PubMed  CAS  Google Scholar 

  • Weatherall DJ, Clegg JB (2002) Genetic variability in response to infection: malaria and after. Genes Immun 3:331–337

    Article  PubMed  CAS  Google Scholar 

  • White NJ (1997) Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 41:1413–1422

    PubMed  CAS  Google Scholar 

  • White NJ (2008) Qinghaosu (artemisinin): the price of success. Science 320:330–334

    Article  PubMed  CAS  Google Scholar 

  • WHO (2009) World Malaria Report. Available athttp://www.who.int/malaria/world_malaria_report_2009/en/index.html

  • WHO (2010) Malaria fact sheet No. 94, April 2010. Available at http://www.who.int/mediacentre/factsheets/fs094/en/index.html

  • Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR (2002) Epidemiology of drug-resistant malaria. Lancet Infect Dis 2:209–218

    Article  PubMed  CAS  Google Scholar 

  • Yeka A, Achan J, D’Alessandro U, Talisuna AO (2009) Quinine monotherapy for treating uncomplicated malaria in the era of artemisinin-based combination therapy: an appropriate public health policy? Lancet Infect Dis 9:448–452

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT et al (1999) Emergence of FY*A(null) in a Plasmodium vivax-endemic region of Papua New Guinea. Proc Natl Acad Sci USA 96:13973–13977

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Biochemistry and Complex Trait Group, McGill University, Montreal, QC, H3G-0B1, Canada

    Gundula Min-Oo & Philippe Gros

  2. Department of Biochemistry and Complex Traits Group, McGill University, Bellini Life Sciences Building, Room 366, 3649 Sir William Osler Promenade, Montreal, QC, H3G-0B1, Canada

    Philippe Gros

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Min-Oo, G., Gros, P. Genetic analysis in mice identifies cysteamine as a novel partner for artemisinin in the treatment of malaria. Mamm Genome 22, 486–494 (2011). https://doi.org/10.1007/s00335-011-9316-8

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