Infection and Drug Resistance (Nov 2022)

Polymorphisms in the K13-Propeller Gene in Artemisinin-Resistant Plasmodium in Mice

  • Zheng S,
  • Liang Y,
  • Wang Z,
  • Liu M,
  • Chen Y,
  • Ai Y,
  • Guo W,
  • Li G,
  • Yuan Y,
  • Xu Z,
  • Wu W,
  • Huang X,
  • Wu Z,
  • Xu Q,
  • Song J,
  • Deng C

Journal volume & issue
Vol. Volume 15
pp. 6533 – 6544

Abstract

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Shaoqin Zheng1,2 *, Yuan Liang2 *, Zhaojia Wang,1 Min Liu,1 Yingyi Chen,1 Ying Ai,1 Wenfeng Guo,1,3 Guoming Li,1 Yueming Yuan,1,2 Zhiyong Xu,2 Wanting Wu,1 Xinan Huang,1,3 Zhibing Wu,3 Qin Xu,1,3 Jianping Song,1,3 Changsheng Deng1,3 1Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Science and Technology Institute, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianping Song; Changsheng Deng, Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China, Tel +86-20-3658 5633 ; +86-20-8746 1723, Email [email protected]; [email protected]: Artemisinin-based combination therapies (ACTs) act as first-line antimalarial drugs and play a crucial role in the successful control of falciparum malaria. However, the recent emergence of resistance of Plasmodium falciparum to ACTs in South East Asia is of particular concern. Hence, there is an urgent need to identify the genetic determinants of and understand the molecular mechanisms underpinning such resistance. Artemisinin resistance (AR) is primarily driven by the mutations in the P. falciparum K13 protein, which is widely recognized as the major molecular marker of AR. However, association of K13 mutations with in vivo AR has been ambiguous due to the absence of a tractable model.Methods: In this study, we have successfully produced artemisinin- and piperaquine-resistant P. berghei K173 following drug administrations. Prolonged parasite clearance and early recrudescence were found following daily exposure to high doses of artemisinin and piperaquine. We have also sequenced the DNA of artemisinin-resistant strains and piperaquine-resistant strains of P. berghei K173 to explore the relationship between PfK13 and AR.Results: The resistance index of P. berghei K173 reached 12.4 after 30 artemisinin-resistant generations, but AR declined gradually after 30 generations. On the 50th generation, the resistance index of artemisinin-resistant strains was only 5.0 compared with the severe drug resistance of piperaquine-resistant strains (I90=148.8). DNA sequencing of artemisinin-resistant strains showed that there were 9 meaningful mutations at P. berghei K13-propeller domain, but the above mutations did not include common clinical point mutations.Conclusion: Our data show that artemisinin is less susceptible to severe resistance compared with other antimalarial drugs. In addition, mutation on P. berghei K13 has a multi-drug-resistant phenotype and may be used as a biomarker to monitor its resistance. More studies need to be conducted on the new mutations detected so as to understand their association, if any, with ACT resistance.Keywords: malaria, Plasmodium berghei, P. berghei K13 gene, artemisinin resistance

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