Advertisement

Acta Parasitologica

, Volume 64, Issue 3, pp 670–678 | Cite as

Infectivity and Screening of Anti-piperaquine Genes in Mice Infected with Piperaquine-Sensitive and Piperaquine-Resistant Plasmodium berghei

  • Guohui Yi
  • Limin Zhou
  • Zhanhong Ye
  • Xianxi Huang
  • Fangli LuEmail author
  • Hong GuoEmail author
Research Article
  • 32 Downloads

Abstract

Background

Piperaquine (PQ) is one of the major components of artemisinin-based combination therapy for malaria. However, the mechanism of PQ resistance has remained unclear.

Methods

In this study, we infected mice with PQ-resistant Plasmodium berghei ANKA strain line (PbPQR) or PQ-sensitive P. berghei ANKA strain line (PbPQS) and their survival rates, parasitemia, and spleen sizes were compared. In addition, we constructed genomic DNA subtractive library of spleens from the infected mice, and screened the potential PQ-resistant related genes from genomic DNA of PbPQR line using the representational difference analysis (RDA) method. Clones of the subtractive library were screened by PCR, and related genes were sequenced and analyzed using BLAST software of NCBI.

Results

Compared to PbPQS-infected mice, PbPQR-infected mice survived significantly longer, and had significantly lowered parasitemia rate and significantly increased splenomegaly. Among the total of 502 clones picked, 494 were sequenced and 96 unique PCR fragments were obtained; in which 24 DNA fragments were homologous to chromosomes related to immune function of mice. ORF Finder blasting showed that at the protein level, 26 encoded proteins were homologous to 18 hypothetical PbANKA proteins and 13 encoded proteins were homologous to “ferlin-like protein” family of PbANKA. In addition, there were more immune-related DNA molecules, ubiquitous PbANKA homology at the ORF fragment level, and enriched ferlin-like protein families identified from PbPQR-infected mice than those from PbPQS-infected mice.

Conclusion

These findings suggest that PbPQR may induce stronger protective immune response than that of PbPQS in infected mice.

Keywords

Plasmodium berghei ANKA Piperaquine resistance Subtractive library Representational difference analysis Ferlin-like protein 

Notes

Funding

Research reported in this publication was supported by the Natural Science Foundation of China (no. 81060140). The content is solely the responsibility of the authors

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

All experiments were performed in compliance with the requirements of the Animal Ethics Committee at Sun Yat-sen University.

References

  1. 1.
    Alaganan A, Singh P, Chitnis CE (2017) Molecular mechanisms that mediate invasion and egress of malaria parasites from red blood cells. Curr Opin Hematol 24:208–214CrossRefGoogle Scholar
  2. 2.
    Allen NL, Penn CW, Hilton AC (2003) Representational difference analysis: critical appraisal and method development for the identification of unique DNA sequences from prokaryotes. J Microbiol Methods 55:73–81CrossRefGoogle Scholar
  3. 3.
    Andrews KT, Fisher G, Skinner-Adams TS (2014) Drug repurposing and human parasitic protozoan diseases. Int Parasitol Drugs Drug Resist 4:95–111CrossRefGoogle Scholar
  4. 4.
    Balato A, Unutmaz D, Gaspari AA (2009) Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. J Investig Dermatol 129:1628–1642CrossRefGoogle Scholar
  5. 5.
    Bartholdson SJ, Crosnier C, Bustamante LY, Rayner JC, Wright GJ (2013) Identifying novel Plasmodium falciparum erythrocyte invasion receptors using systematic extracellular protein interaction screens. Cell Microbiol 15:1304–1312CrossRefGoogle Scholar
  6. 6.
    Boyle MJ, Wilson DW, Beeson JG (2013) New approaches to studying Plasmodium falciparum merozoite invasion and insights into invasion biology. Int J Parasitol 43:1–10CrossRefGoogle Scholar
  7. 7.
    Chen L, Qu FY, Zhou YC (1982) Field observations on the antimalarial piperaquine. Chin Med J (Engl) 95:281–286Google Scholar
  8. 8.
    Davis TM, Hung TY, Sim IK, Karunajeewa HA, Ilett KF (2005) Piperaquine: a resurgent antimalarial drug. Drugs 65:75–87CrossRefGoogle Scholar
  9. 9.
    Del PH, Ferrer M, Brugat T, Martin-Jaular L, Langhorne J, Lacerda MV (2012) The role of the spleen in malaria. Cell Microbiol 14:343–355CrossRefGoogle Scholar
  10. 10.
    Ferrer M, Martin-Jaular L, De Niz M, Khan SM, Janse CJ, Calvo M, Heussler V, Del PH (2014) Imaging of the spleen in malaria. Parasitol Int 63:195–205CrossRefGoogle Scholar
  11. 11.
    Goodman CD, McFadden GI (2013) Targeting apicoplasts in malaria parasites. Expert Opin Ther Targets 17:167–177CrossRefGoogle Scholar
  12. 12.
    Guo H, Sun S, Finan TM, Xu J (2005) Novel DNA sequences from natural strains of the nitrogen-fixing symbiotic bacterium Sinorhizobium meliloti. Appl Environ Microbiol 71:7130–7138CrossRefGoogle Scholar
  13. 13.
    Ha YR, Kang YJ, Lee SJ (2015) In vivo study on splenomegaly inhibition by genistein in Plasmodium berghei-infected mice. Parasitol Int 64:369–376CrossRefGoogle Scholar
  14. 14.
    Hall N, Karras M, Raine JD, Carlton JM, Kooij TW, Berriman M, Florens L, Janssen CS, Pain A, Christophides GK, James K, Rutherford K, Harris B, Harris D, Churcher C, Quail MA, Ormond D, Doggett J, Trueman HE, Mendoza J, Bidwell SL, Rajandream MA, Carucci DJ, Yates JR, Kafatos FC, Janse CJ, Barrell B, Turner CM, Waters AP, Sinden RE (2005) A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses. Science 307:82–86CrossRefGoogle Scholar
  15. 15.
    Huang XX, Zhou LM, Yi GH, Wu JY, Pan ZY, Xue WL, Guo H (2012) Immunological analysis of piperaquine-resistant murine model of Plasmodium berghei ANKA strain. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 30(12–16):19Google Scholar
  16. 16.
    Hung TY, Davis TM, Ilett KF, Karunajeewa H, Hewitt S, Denis MB, Lim C, Socheat D (2004) Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol 57:253–262CrossRefGoogle Scholar
  17. 17.
    Jeffares DC, Pain A, Berry A, Cox AV, Stalker J, Ingle CE, Thomas A, Quail MA, Siebenthall K, Uhlemann AC, Kyes S, Krishna S, Newbold C, Dermitzakis ET, Berriman M (2007) Genome variation and evolution of the malaria parasite Plasmodium falciparum. Nat Genet 39:120–125CrossRefGoogle Scholar
  18. 18.
    Karema C, Fanello CI, van Overmeir C, van Geertruyden JP, van Doren W, Ngamije D, D’Alessandro U (2006) Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg 100:1105–1111CrossRefGoogle Scholar
  19. 19.
    Kasturi K, Mallika DS, Amos SJ, Venkateshaiah P, Rao KS (2012) Current opinion on an emergence of drug resistant strains of Plasmodium falciparum through genetic alterations. Bioinformation 8:1114–1118CrossRefGoogle Scholar
  20. 20.
    Keating GM (2012) Dihydroartemisinin/piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. Drugs 72:937–961CrossRefGoogle Scholar
  21. 21.
    Lau LS, Fernandez-Ruiz D, Mollard V, Sturm A, Neller MA, Cozijnsen A, Gregory JL, Davey GM, Jones CM, Lin YH, Haque A, Engwerda CR, Nie CQ, Hansen DS, Murphy KM, Papenfuss AT, Miles JJ, Burrows SR, de Koning-Ward T, McFadden GI, Carbone FR, Crabb BS, Heath WR (2014) CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria. PLoS Pathog 10:e1004135CrossRefGoogle Scholar
  22. 22.
    Liu DQ (2014) Surveillance of antimalarial drug resistance in China in the 1980s–1990s. Infect Dis Poverty 3:8CrossRefGoogle Scholar
  23. 23.
    Martins YC, Smith MJ, Pelajo-Machado M, Werneck GL, Lenzi HL, Daniel-Ribeiro CT, Carvalho LJ (2009) Characterization of cerebral malaria in the outbred Swiss Webster mouse infected by Plasmodium berghei ANKA. Int J Exp Pathol 90:119–130CrossRefGoogle Scholar
  24. 24.
    Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, Rahim-Awab G, Barnadas C, Berry A, Boum Y, Bustos MD, Cao J, Chen JH, Collet L, Cui L, Thakur GD, Dieye A, Djalle D, Dorkenoo MA, Eboumbou-Moukoko CE, Espino FE, Fandeur T, Ferreira-da-Cruz MF, Fola AA, Fuehrer HP, Hassan AM, Herrera S, Hongvanthong B, Houze S, Ibrahim ML, Jahirul-Karim M, Jiang L, Kano S, Ali-Khan W, Khanthavong M, Kremsner PG, Lacerda M, Leang R, Leelawong M, Li M, Lin K, Mazarati JB, Menard S, Morlais I, Muhindo-Mavoko H, Musset L, Na-Bangchang K, Nambozi M, Niare K, Noedl H, Ouedraogo JB, Pillai DR, Pradines B, Quang-Phuc B, Ramharter M, Randrianarivelojosia M, Sattabongkot J, Sheikh-Omar A, Silue KD, Sirima SB, Sutherland C, Syafruddin D, Tahar R, Tang LH, Toure OA, Tshibangu-wa-Tshibangu P, Vigan-Womas I, Warsame M, Wini L, Zakeri S, Kim S, Eam R, Berne L, Khean C, Chy S, Ken M, Loch K, Canier L, Duru V, Legrand E, Barale JC, Stokes B, Straimer J, Witkowski B, Fidock DA, Rogier C, Ringwald P, Ariey F, Mercereau-Puijalon O (2016) A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med 374:2453–2464CrossRefGoogle Scholar
  25. 25.
    Moore BR, Ilett KF, Page-Sharp M, Jago JD, Batty KT (2009) Piperaquine pharmacodynamics and parasite viability in a murine malaria model. Antimicrob Agents Chemother 53:2707–2713CrossRefGoogle Scholar
  26. 26.
    Paul AS, Egan ES, Duraisingh MT (2015) Host–parasite interactions that guide red blood cell invasion by malaria parasites. Curr Opin Hematol 22:220–226CrossRefGoogle Scholar
  27. 27.
    Riglar DT, Richard D, Wilson DW, Boyle MJ, Dekiwadia C, Turnbull L, Angrisano F, Marapana DS, Rogers KL, Whitchurch CB, Beeson JG, Cowman AF, Ralph SA, Baum J (2011) Super-resolution dissection of coordinated events during malaria parasite invasion of the human erythrocyte. Cell Host Microbe 9:9–20CrossRefGoogle Scholar
  28. 28.
    Salinas ND, Tolia NH (2016) Red cell receptors as access points for malaria infection. Curr Opin Hematol 23:215–223CrossRefGoogle Scholar
  29. 29.
    Satchwell TJ (2016) Erythrocyte invasion receptors for Plasmodium falciparum: new and old. Transfus Med 26:77–88CrossRefGoogle Scholar
  30. 30.
    Subrahmanyam PB, Sun W, East JE, Li J, Webb TJ (2012) Natural killer T cell based immunotherapy. J Vaccines Vaccin 3:144CrossRefGoogle Scholar
  31. 31.
    Tran TH, Dolecek C, Pham PM, Nguyen TD, Nguyen TT, Le HT, Dong TH, Tran TT, Stepniewska K, White NJ, Farrar J (2004) Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 363:18–22CrossRefGoogle Scholar
  32. 32.
    Valecha N, Krudsood S, Tangpukdee N, Mohanty S, Sharma SK, Tyagi PK, Anvikar A, Mohanty R, Rao BS, Jha AC, Shahi B, Singh JP, Roy A, Kaur P, Kothari M, Mehta S, Gautam A, Paliwal JK, Arora S, Saha N (2012) Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated Plasmodium falciparum malaria: a comparative, multicenter, randomized clinical trial. Clin Infect Dis 55:663–671CrossRefGoogle Scholar
  33. 33.
    Volkman SK, Sabeti PC, DeCaprio D, Neafsey DE, Schaffner SF, Milner DJ, Daily JP, Sarr O, Ndiaye D, Ndir O, Mboup S, Duraisingh MT, Lukens A, Derr A, Stange-Thomann N, Waggoner S, Onofrio R, Ziaugra L, Mauceli E, Gnerre S, Jaffe DB, Zainoun J, Wiegand RC, Birren BW, Hartl DL, Galagan JE, Lander ES, Wirth DF (2007) A genome-wide map of diversity in Plasmodium falciparum. Nat Genet 39:113–119CrossRefGoogle Scholar
  34. 34.
    Wellems TE, Walker-Jonah A, Panton LJ (1991) Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc Natl Acad Sci USA 88:3382–3386CrossRefGoogle Scholar
  35. 35.
    Whegang YS, Tahar R, Basco LK (2017) Comparison of anti-malarial drugs efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis. Malar J 16:311CrossRefGoogle Scholar
  36. 36.
    White NJ, Olliaro PL (1996) Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitol Today 12:399–401CrossRefGoogle Scholar
  37. 37.
    World Health Organization (2018) World malaria report. World Health Organization, GenevaGoogle Scholar

Copyright information

© Witold Stefański Institute of Parasitology, Polish Academy of Sciences 2019

Authors and Affiliations

  1. 1.Public Research LaboratoryHainan Medical UniversityHaikouChina
  2. 2.Department of Parasitology, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina
  3. 3.Key Laboratory of Tropical Disease Control of Ministry of EducationSun Yat-sen UniversityGuangzhouChina

Personalised recommendations