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<p>The genetic basis of <i>Plasmodium falciparum</i> resistance to quinine, a drug used to treat severe malaria, has long been unclear. To investigate this, here we used a human liver-chimaeric mouse model to conduct a <i>P. falciparum</i> genetic cross between quinine-partially resistant and quinine-sensitive parasites. Drug profiling and quantitative trait loci analyses of 120 unique recombinant progeny mapped resistance to segments on chromosomes 7 and 12, indicating a polygenic basis. The chloroquine resistance transporter PfCRT and a structurally similar putative drug/metabolite transporter, DMT1, were identified as primary chromosome 7 candidates based on gene-editing studies. In a proteoliposome assay, both mutant DMT1 and PfCRT transported more quinine than their wild-type isoforms. DMT1 localized to the <i>P. falciparum</i> digestive vacuole, lipid bodies, parasitophorous vacuolar membrane and structures associated with vesicular trafficking. An ATP-dependent zinc metalloprotease (FtsH1) on chromosome 12 also modulated quinine and chloroquine resistance. We suggest that genotypic surveillance of these markers should be performed in clinical settings of quinine use.</p>

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Identification of genetic markers of quinine partial resistance in Plasmodium falciparum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Mariko Kanai,
  • Sachel Mok,
  • Tomas Yeo,
  • Melanie J. Shears,
  • Jin H. Jeon,
  • Sunil K. Narwal,
  • Leila S. Ross,
  • Kharizta Wiradiputri,
  • Meseret T. Haile,
  • Abhai K. Tripathi,
  • Godfree Mlambo,
  • Jonathan Kim,
  • Eva Gil-Iturbe,
  • Heekuk Park,
  • Tolla Ndiaye,
  • John Okombo,
  • Kurt E. Ward,
  • Felix D. Rozenberg,
  • Kate J. Fairhurst,
  • Sydney M. Gavula,
  • Talia S. Bloxham,
  • Jessica L. Bridgford,
  • Tanaya Sheth,
  • Manuel Llinás,
  • Marcus C. S. Lee,
  • Jennifer L. Small-Saunders,
  • Filippo Mancia,
  • Matthias Quick,
  • Anne-Catrin Uhlemann,
  • Photini Sinnis,
  • David Armand Fidock

摘要

The genetic basis of Plasmodium falciparum resistance to quinine, a drug used to treat severe malaria, has long been unclear. To investigate this, here we used a human liver-chimaeric mouse model to conduct a P. falciparum genetic cross between quinine-partially resistant and quinine-sensitive parasites. Drug profiling and quantitative trait loci analyses of 120 unique recombinant progeny mapped resistance to segments on chromosomes 7 and 12, indicating a polygenic basis. The chloroquine resistance transporter PfCRT and a structurally similar putative drug/metabolite transporter, DMT1, were identified as primary chromosome 7 candidates based on gene-editing studies. In a proteoliposome assay, both mutant DMT1 and PfCRT transported more quinine than their wild-type isoforms. DMT1 localized to the P. falciparum digestive vacuole, lipid bodies, parasitophorous vacuolar membrane and structures associated with vesicular trafficking. An ATP-dependent zinc metalloprotease (FtsH1) on chromosome 12 also modulated quinine and chloroquine resistance. We suggest that genotypic surveillance of these markers should be performed in clinical settings of quinine use.