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Background <p>Cross-border parasite movement drives resistance emergence in endemic regions. In Uganda, <i>Plasmodium falciparum</i> with artemisinin partial resistance emerged early and spread rapidly, making it a focal point for surveillance. In northeastern Democratic Republic of Congo (DRC), a key trade corridor bordering Uganda, we investigated molecular markers of artemisinin partial resistance and resistance to partner drugs used in artemisinin-based combination therapies (ACTs). Monitoring these resistance markers in DRC is essential for guiding regional containment efforts.</p> Methods <p>From May to June 2023, we conducted active and passive malaria case detection in 20 villages and a central hospital, respectively. Molecular analyses included copy number variation (CNV) in <i>pfmdr1</i> and <i>pfpm2/3</i>, and genotyping of <i>pfkelch13</i>, <i>pfmdr1</i>, and <i>pfcrt</i>. For <i>pfmdr1</i> CNV determination, we adopted a quantitative real-time PCR threshold of 1.4, recently proposed for parasite populations with frequent multiclonal infections. Whole-genome sequencing (WGS) was performed on hospital-derived samples to assess parasite relatedness and trace resistance spread.</p> Results <p>Among the 536 individuals sampled from the villages, 49.8% tested positive for <i>P. falciparum</i> by PCR. The <i>pfmdr1</i> N86 allele was fixed, and 50.3% of samples carried the N<Emphasis Type="Underline">F</Emphasis>D haplotype (amino acid positions 86, 184, and 1246), a marker associated with reduced lumefantrine susceptibility in Africa. <i>Pfmdr1</i> CNV was detected in 4.4% of samples using the conventional threshold (≥ 1.5), increasing to 11.7% with the 1.4 threshold. <i>Pfpm2/3</i> CNVs, which may influence piperaquine susceptibility, were identified in 7.0% of samples. The validated <i>pfkelch13</i> mutations A675V and C469Y, associated with artemisinin partial resistance, were detected in 4.3% and 1.3% of village samples, respectively. Principal component analysis of WGS data showed that DRC parasites carrying A675V or C469Y clustered closely with Ugandan strains, supporting cross-border spread of resistant parasites between DRC and Uganda.</p> Conclusion <p>Our findings identified the presence of molecular markers associated with artemisinin partial resistance and reduced susceptibility to lumefantrine in northeastern DRC, along with evidence of cross-border parasite migration from Uganda. Given opposing selection pressures of lumefantrine and amodiaquine on <i>pfmdr1</i> and <i>pfcrt</i>, alternative ACTs such as artesunate-amodiaquine may merit further evaluation. To sustain ACT efficacy, integrated genomic surveillance, clinical monitoring, and coordinated regional policy responses are essential.</p>

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Cross-border molecular epidemiology of Plasmodium falciparum drug susceptibility: insights from the Uganda–Democratic Republic of the Congo border

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Patrick Mamona Dilufwasayo,
  • Betty Balikagala,
  • Moise Agenowun Uchopa,
  • Jacques Amanga Amaa,
  • Dieudonné Mumba Ngoyi,
  • Toshihiro Mita

摘要

Background

Cross-border parasite movement drives resistance emergence in endemic regions. In Uganda, Plasmodium falciparum with artemisinin partial resistance emerged early and spread rapidly, making it a focal point for surveillance. In northeastern Democratic Republic of Congo (DRC), a key trade corridor bordering Uganda, we investigated molecular markers of artemisinin partial resistance and resistance to partner drugs used in artemisinin-based combination therapies (ACTs). Monitoring these resistance markers in DRC is essential for guiding regional containment efforts.

Methods

From May to June 2023, we conducted active and passive malaria case detection in 20 villages and a central hospital, respectively. Molecular analyses included copy number variation (CNV) in pfmdr1 and pfpm2/3, and genotyping of pfkelch13, pfmdr1, and pfcrt. For pfmdr1 CNV determination, we adopted a quantitative real-time PCR threshold of 1.4, recently proposed for parasite populations with frequent multiclonal infections. Whole-genome sequencing (WGS) was performed on hospital-derived samples to assess parasite relatedness and trace resistance spread.

Results

Among the 536 individuals sampled from the villages, 49.8% tested positive for P. falciparum by PCR. The pfmdr1 N86 allele was fixed, and 50.3% of samples carried the NFD haplotype (amino acid positions 86, 184, and 1246), a marker associated with reduced lumefantrine susceptibility in Africa. Pfmdr1 CNV was detected in 4.4% of samples using the conventional threshold (≥ 1.5), increasing to 11.7% with the 1.4 threshold. Pfpm2/3 CNVs, which may influence piperaquine susceptibility, were identified in 7.0% of samples. The validated pfkelch13 mutations A675V and C469Y, associated with artemisinin partial resistance, were detected in 4.3% and 1.3% of village samples, respectively. Principal component analysis of WGS data showed that DRC parasites carrying A675V or C469Y clustered closely with Ugandan strains, supporting cross-border spread of resistant parasites between DRC and Uganda.

Conclusion

Our findings identified the presence of molecular markers associated with artemisinin partial resistance and reduced susceptibility to lumefantrine in northeastern DRC, along with evidence of cross-border parasite migration from Uganda. Given opposing selection pressures of lumefantrine and amodiaquine on pfmdr1 and pfcrt, alternative ACTs such as artesunate-amodiaquine may merit further evaluation. To sustain ACT efficacy, integrated genomic surveillance, clinical monitoring, and coordinated regional policy responses are essential.