The many paths to artemisinin resistance in Plasmodium falciparum

World Health Organization, 2022 Beeson, 2022, The RTS,S malaria vaccine: current impact and foundation for the future, Sci. Transl. Med., 14, 10.1126/scitranslmed.abo6646 Blasco, 2017, Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic, Nat. Med., 23, 917, 10.1038/nm.4381 White, 2008, Qinghaosu (artemisinin): the price of success, Science, 320, 330, 10.1126/science.1155165 World Health Organization, 2015 van der Pluijm, 2021, Triple artemisinin-based combination therapies for malaria – a new paradigm?, Trends Parasitol., 37, 15, 10.1016/j.pt.2020.09.011 Das, 2019, Novel Pfkelch13 gene polymorphism associates with artemisinin resistance in Eastern India, Clin. Infect. Dis., 69, 1144, 10.1093/cid/ciy1038 World Health Organization, 2022 van der Pluijm, 2020, Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial, Lancet, 395, 1345, 10.1016/S0140-6736(20)30552-3 Khoury, 2020, Artemisinin resistance and the unique selection pressure of a short-acting antimalarial, Trends Parasitol., 36, 884, 10.1016/j.pt.2020.07.004 Witkowski, 2013, Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in vitro and ex vivo drug-response studies, Lancet Infect. Dis., 13, 1043, 10.1016/S1473-3099(13)70252-4 Dondorp, 2009, Artemisinin resistance in Plasmodium falciparum malaria, N. Engl. J. Med., 361, 455, 10.1056/NEJMoa0808859 Noedl, 2008, Evidence of artemisinin-resistant malaria in Western Cambodia, N. Engl. J. Med., 359, 2619, 10.1056/NEJMc0805011 Ariey, 2013, A molecular marker of artemisinin-resistant Plasmodium falciparum malaria, Nature, 505, 50, 10.1038/nature12876 Stokes, 2021, Plasmodium falciparum k13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness, eLife, 10, 10.7554/eLife.66277 Straimer, 2015, K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates, Science, 347, 428, 10.1126/science.1260867 Ashley, 2014, Spread of artemisinin resistance in Plasmodium falciparum malaria, N. Engl. J. Med., 371, 411, 10.1056/NEJMoa1314981 Miotto, 2015, Genetic architecture of artemisinin-resistant Plasmodium falciparum, Nat. Genet., 47, 226, 10.1038/ng.3189 Amato, 2018, Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study, Lancet Infect. Dis., 18, 337, 10.1016/S1473-3099(18)30068-9 Uwimana, 2020, Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda, Nat. Med., 26, 1602, 10.1038/s41591-020-1005-2 Balikagala, 2021, Evidence of artemisinin-resistant malaria in Africa, N. Engl. J. Med., 385, 1163, 10.1056/NEJMoa2101746 Das, 2018, Evidence of artemisinin-resistant Plasmodium falciparum Malaria in Eastern India, N. Engl. J. Med., 379, 1962, 10.1056/NEJMc1713777 World Health Organization, 2020 Bhattacharjee, 2018, Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance, Blood, 131, 1234, 10.1182/blood-2017-11-814665 Birnbaum, 2020, A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites, Science, 367, 51, 10.1126/science.aax4735 Gnädig, 2020, Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13, PLoS Pathog., 16, 10.1371/journal.ppat.1008482 Yang, 2019, Decreased K13 abundance reduces hemoglobin catabolism and proteotoxic stress, underpinning artemisinin resistance, Cell Rep., 29, 2917, 10.1016/j.celrep.2019.10.095 Tutor, 2023, The Plasmodium falciparum artemisinin resistance-associated protein Kelch 13 is required for formation of normal cytostomes, eLife, 12 Behrens, 2023, Impact of different mutations on Kelch13 protein levels, ART resistance and fitness cost in Plasmodium falciparum parasites, bioRxiv Mok, 2015, Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance, Science, 347, 431, 10.1126/science.1260403 Rocamora, 2018, Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites, PLoS Pathog., 14, 10.1371/journal.ppat.1006930 Zhu, 2022, Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response, Commun. Biol., 5, 274, 10.1038/s42003-022-03215-0 Dogovski, 2015, Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance, PLoS Biol., 13, 10.1371/journal.pbio.1002132 Zhang, 2017, Inhibiting the Plasmodium eIF2α kinase PK4 prevents artemisinin-induced latency, Cell Host Microbe, 22, 766, 10.1016/j.chom.2017.11.005 Bridgford, 2018, Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome, Nat. Commun., 9, 3801, 10.1038/s41467-018-06221-1 Behrens, 2021, The newly discovered role of endocytosis in artemisinin resistance, Med. Res. Rev., 41, 2998, 10.1002/med.21848 Tilley, 2016, Artemisinin action and resistance in Plasmodium falciparum, Trends Parasitol., 32, 682, 10.1016/j.pt.2016.05.010 Cullinan, 2003, Nrf2 Is a direct PERK substrate and effector of PERK-dependent cell survival, Mol. Cell. Biol., 23, 7198, 10.1128/MCB.23.20.7198-7209.2003 Mbengue, 2015, A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria, Nature, 520, 683, 10.1038/nature14412 Ray, 2022, Autophagy underlies the proteostasis mechanisms of artemisinin resistance in P. falciparum malaria, mBio, 13, 10.1128/mbio.00630-22 Breglio, 2018, A single nucleotide polymorphism in the Plasmodium falciparum atg18 gene associates with artemisinin resistance and confers enhanced parasite survival under nutrient deprivation, Malar. J., 17, 391, 10.1186/s12936-018-2532-x Kannan, 2023, Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites, Cell Death Discov., 9, 160, 10.1038/s41420-023-01401-5 Burman, 2010, Regulation of autophagy by phosphatidylinositol 3-phosphate, FEBS Lett., 584, 1302, 10.1016/j.febslet.2010.01.011 Bernales, 2006, Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response, PLoS Biol., 4, 10.1371/journal.pbio.0040423 Mesén-Ramírez, 2021, The parasitophorous vacuole nutrient channel is critical for drug access in malaria parasites and modulates the artemisinin resistance fitness cost, Cell Host Microbe, 29, 1774, 10.1016/j.chom.2021.11.002 Rawat, 2022, Identification of co-existing mutations and gene expression trends associated with K13-mediated artemisinin resistance in Plasmodium falciparum, Front. Genet., 13, 10.3389/fgene.2022.824483 Rawat, 2021, Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum, Sci. Rep., 11, 852, 10.1038/s41598-020-79539-w Kanyal, 2022, PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum, bioRxiv Tintó-Font, 2021, A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures, Nat. Microbiol., 6, 1163, 10.1038/s41564-021-00940-w Lucky, 2023, Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses, Antimicrob. Agents Chemother., 67, 10.1128/aac.00577-23 Carey, 2017, Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance, BMC Genomics, 18, 543, 10.1186/s12864-017-3905-1 Mok, 2021, Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival, Nat. Commun., 12, 530, 10.1038/s41467-020-20805-w Siddiqui, 2017, Multi-omics based identification of specific biochemical changes associated with PfKelch13-mutant artemisinin-resistant Plasmodium falciparum, J. Infect. Dis., 215, 1435, 10.1093/infdis/jix156 Yu, 2023, Ring-stage growth arrest: metabolic basis of artemisinin tolerance in Plasmodium falciparum, iScience, 26 Chen, 2023, Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum, Drug Resist. Updat., 70, 10.1016/j.drup.2023.100978 Yoo, 2022, Amino acid metabolism in cancer drug resistance, Cells, 11, 140, 10.3390/cells11010140 Straimer, 2017, Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro, mBio, 8, 10, 10.1128/mBio.00172-17 Amato, 2016, Genomic epidemiology of artemisinin resistant malaria, eLife, 5 Mukherjee, 2017, Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia, Malar. J., 16, 195, 10.1186/s12936-017-1845-5 Das, 2021, Artemisinin combination therapy fails even in the absence of Plasmodium falciparum kelch13 gene polymorphism in Central India, Sci. Rep., 11, 9946, 10.1038/s41598-021-89295-0 Nima, 2022, Assessment of Plasmodium falciparum artemisinin resistance independent of kelch13 polymorphisms and with escalating malaria in Bangladesh, mBio, 13, 10.1128/mbio.03444-21 Demas, 2018, Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility, Proc. Natl. Acad. Sci. U. S. A., 115, 12799, 10.1073/pnas.1812317115 Henrici, 2020, Modification of pfap2μ and pfubp1 markedly reduces ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro, Antimicrob. Agents Chemother., 64 Kubota, 2022, Evaluation of the effect of gene duplication by genome editing on drug resistance in Plasmodium falciparum, Front. Cell. Infect. Microbiol., 12, 10.3389/fcimb.2022.915656 Sutherland, 2017, pfk13-Independent treatment failure in four imported cases of Plasmodium falciparum malaria treated with artemether-lumefantrine in the United Kingdom, Antimicrob. Agents Chemother., 61, 10.1128/AAC.02382-16 Choubey, 2023, Genomic analysis of Indian isolates of Plasmodium falciparum: implications for drug resistance and virulence factors, Int. J. Parasitol. Drugs Drug Resist., 22, 52, 10.1016/j.ijpddr.2023.05.003 Goldman, 2019, The impact of heterogeneity on single-cell sequencing, Front. Genet., 10, 8, 10.3389/fgene.2019.00008 Davis, 2016, Defining heterogeneity within bacterial populations via single cell approaches, BioEssays, 38, 782, 10.1002/bies.201500121 Mackinnon, 2009, Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates, PLoS Pathog., 5, 10.1371/journal.ppat.1000644 Rovira-Graells, 2012, Transcriptional variation in the malaria parasite Plasmodium falciparum, Genome Res., 22, 925, 10.1101/gr.129692.111 Rawat, 2021, Single-cell RNA sequencing reveals cellular heterogeneity and stage transition under temperature stress in synchronized Plasmodium falciparum cells, Microbiol. Spectr., 9, 10.1128/Spectrum.00008-21 Dave, 2022, Pervasive sequence-level variation in the transcriptome of Plasmodium falciparum, NAR Genomics Bioinforma., 4, 10.1093/nargab/lqac036 Peatey, 2015, Mitochondrial membrane potential in a small subset of artemisinin-induced dormant Plasmodium falciparum parasites in vitro, J. Infect. Dis., 212, 426, 10.1093/infdis/jiv048 Talman, 2019, Artemisinin bioactivity and resistance in malaria parasites, Trends Parasitol., 35, 953, 10.1016/j.pt.2019.09.005 Witkowski, 2010, Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism, Antimicrob. Agents Chemother., 54, 1872, 10.1128/AAC.01636-09 Wellems, 2020, ‘Artemisinin resistance’: something new or old? Something of a misnomer?, Trends Parasitol., 36, 735, 10.1016/j.pt.2020.05.013 Tripathi, 2023, The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular senescence and drug resilience, bioRxiv Duvalsaint, 2018, Phytohormones, isoprenoids, and role of the apicoplast in recovery from dihydroartemisinin-induced dormancy of Plasmodium falciparum, Antimicrob. Agents Chemother., 62, 10.1128/AAC.01771-17 Nötzel, 2022, PfD123 modulates K13-mediated survival and recovery after artemisinin exposure, bioRxiv Fang, 2004, Ambient glucose concentration and gene expression in Plasmodium falciparum, Mol. Biochem. Parasitol., 133, 125, 10.1016/j.molbiopara.2003.09.004 Kwiatkowski, 1989, Febrile temperatures can synchronize the growth of Plasmodium falciparum in vitro, J. Exp. Med., 169, 357, 10.1084/jem.169.1.357 Vasquez, 2021, Oxidative stress and pathogenesis in malaria, Front. Cell. Infect. Microbiol., 11, 10.3389/fcimb.2021.768182 Mancio-Silva, 2017, Nutrient sensing modulates malaria parasite virulence, Nature, 547, 213, 10.1038/nature23009 Kumar, 2021, Linking nutrient sensing and gene expression in Plasmodium falciparum blood-stage parasites, Mol. Microbiol., 115, 891, 10.1111/mmi.14652 Rawat, 2020, Role of PfGCN5 in nutrient sensing and transcriptional regulation in Plasmodium falciparum, J. Biosci., 45, 11, 10.1007/s12038-019-9981-4 Brown, 2023, Nutrient limitation mimics artemisinin tolerance in malaria, mBio, 14, 10.1128/mbio.00705-23 Zhang, 2021, The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite, Nat. Commun., 12, 4563, 10.1038/s41467-021-24814-1 Henrici, 2019, Transient temperature fluctuations severely decrease P. falciparum susceptibility to artemisinin in vitro, Int. J. Parasitol. Drugs Drug Resist., 9, 23, 10.1016/j.ijpddr.2018.12.003 Ismail, 2016, Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7, Proc. Natl. Acad. Sci. U. S. A., 113, 2080, 10.1073/pnas.1600459113