Temporal organization of the Plasmodium falciparum transcriptome prioritises genetic polymorphisms associated with artemisinin response

Abstract Artemisinin-based combination therapies (ACTs) have substantially reduced the global burden of malaria, but the emergence and spread of artemisinin partial resistance (ART-R) threatens these gains. Although mutations in Plasmodium falciparum kelch13 (pfk13) are established mediators of ART-R, they do not fully explain variation in parasite responses, highlighting the need for complementary markers. We integrated six independent intra-erythrocytic developmental cycle (IDC) transcriptomic datasets by harmonic regression and random-effects meta-analysis, followed by network analyses, protein structural modelling, population genomics and ex vivo dihydroartemisinin susceptibility data, to identify candidate P. falciparum polymorphisms associated with artemisinin response. The meta-analysis identified 2,842 of 5,292 genes as significantly rhythmic across the 48-hour IDC, including those encoding PfK13 and PfMDR1. Integration with whole-genome sequences of Ugandan field isolates prioritized 13 nonsynonymous variants across 10 genes, encoding PfAP2-G, PfPX1, PfACS7, PfACS1a, PfRESA3, PfDRPC and PfA8IJP together with three proteins of unknown function, all transcriptionally co-timed with pfk13. Polymorphisms in pfpx1 have independently been implicated in artemisinin susceptibility, consistent with our prioritization. These candidates are potential complementary mediators of artemisinin response. Beyond them, the pipeline itself is transferable to other resistance phenotypes and periodic transcriptional programmes.

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Publication Details

Journal
Research Square
Published
2026-11-04
DOI
https://doi.org/10.21203/rs.3.rs-11552900/v1
Primary Topic
Malaria Research and Control
Type
preprint
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preprint

Temporal organization of the Plasmodium falciparum transcriptome prioritises genetic polymorphisms associated with artemisinin response

Karamoko Niaré, Victor Asua, Fredrick Elishama Kakembo, Thomas Katairo et al.
Research Square
Malaria Research and Control
preprint

Temporal organization of the Plasmodium falciparum transcriptome prioritises genetic polymorphisms associated with artemisinin response

Karamoko Niaré, Victor Asua, Fredrick Elishama Kakembo, Thomas Katairo, Jessica J. Briggs, Stephen Orena, Daudi Jjingo, Joaniter Immaculate Nankabirwa, Emmanuel Arinaitwe, Ronald M. Galiwango, Martin Okitwi, Philip Jon Rosenthal, Moses Robert Kamya, Grace Kebirungi, Isaac Ssewanyana, Shahiid Kiyaga, Andrew Walakira, David Twesigomwe, Stephen Tukwasibwe, Kevin Cissy Nabukeera, Syrus Semawule, Brenda Namugamba, Samuel Nsobya, Edith Nabukenya, Joseph Nyanzi, Melisa D. Conrad
preprint en

Abstract

Abstract Artemisinin-based combination therapies (ACTs) have substantially reduced the global burden of malaria, but the emergence and spread of artemisinin partial resistance (ART-R) threatens these gains. Although mutations in Plasmodium falciparum kelch13 (pfk13) are established mediators of ART-R, they do not fully explain variation in parasite responses, highlighting the need for complementary markers. We integrated six independent intra-erythrocytic developmental cycle (IDC) transcriptomic datasets by harmonic regression and random-effects meta-analysis, followed by network analyses, protein structural modelling, population genomics and ex vivo dihydroartemisinin susceptibility data, to identify candidate P. falciparum polymorphisms associated with artemisinin response. The meta-analysis identified 2,842 of 5,292 genes as significantly rhythmic across the 48-hour IDC, including those encoding PfK13 and PfMDR1. Integration with whole-genome sequences of Ugandan field isolates prioritized 13 nonsynonymous variants across 10 genes, encoding PfAP2-G, PfPX1, PfACS7, PfACS1a, PfRESA3, PfDRPC and PfA8IJP together with three proteins of unknown function, all transcriptionally co-timed with pfk13. Polymorphisms in pfpx1 have independently been implicated in artemisinin susceptibility, consistent with our prioritization. These candidates are potential complementary mediators of artemisinin response. Beyond them, the pipeline itself is transferable to other resistance phenotypes and periodic transcriptional programmes.

Research Square
Johns Hopkins University (US), University of California, San Francisco (US), Brown University (US), Infectious Diseases Institute (UG), Infectious Diseases Research Collaboration (UG), African Field Epidemiology Network (UG), MRC/UVRI & LSHTM Uganda Research Unit (UG), Makerere University (UG), University of Tübingen (DE), Uganda Virus Research Institute (UG)
Malaria Research and Control
DOIOpen Access PDFOpenAlex
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