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PubMed2026

Versatile, marker-free platform for life cycle-wide imaging of Plasmodium falciparum by integrating an exogenous gene cassette into a conserved intergenic locus.

The creation of transgenic Plasmodium falciparum lines with robust fluorescence across the entire life cycle is essential for advancing our understanding of parasite biology, which in turn informs the development of new drugs and vaccines. In this study, we utilized Plasmodium-optimized genome editing to integrate an mCherry expression cassette into a selected intergenic locus without gene disruption. The resulting marker-free line, NF54-mCh, exhibited intense fluorescence throughout all developmental stages, including asexual and sexual blood stages, as well as mosquito (ookinete, oocyst, and sporozoite) and liver stages. NF54-mCh showed normal proliferation, gametocytogenesis, and efficient transmission to mosquitoes. The ultra-high brightness in salivary gland sporozoites allowed for the non-invasive identification of infected mosquitoes. Sporozoites remained highly infectious to humanized mouse livers, thus enabling the completion of the full life cycle. NF54-mCh serves as a parental line for performing additional genetic modifications, because the CRISPR/Cas9-based genome editing method is free of introduced drug resistance markers. The broader applicability of this strategy was validated by generating similar reporter lines in Plasmodium species utilized in rodent malaria models. In summary, NF54-mCh represents a unique, versatile platform that will accelerate fundamental research and support the future development of malaria control strategies, including new vaccines and drugs.

Animals↗

PubMed2025

Plasmodium falciparum CyRPA Glycan Binding Does Not Explain Adaptation to Humans.

The human malaria parasite Plasmodium falciparum evolved from a parasite that infects gorillas, termed Plasmodium praefalciparum. The sialic acids on glycans on the surface of erythrocytes differ between humans and other apes. It has recently been shown that the P. falciparum cysteine-rich protective antigen (PfCyRPA) binds human sialoglycans as an essential step in the erythrocyte invasion pathway, while that of the chimpanzee parasite, Plasmodium reichenowi has affinities matching ape glycans. Two amino acid changes, at sites 154 and 209, were shown to be sufficient to switch glycan binding preferences and inferred to reflect adaptation of P. falciparum to humans. However, we show that sites 154 and 209 are identical in P. falciparum and P. praefalciparum, with no other differences located in or near the CyRPA glycan binding sites. Thus, the gorilla precursor appears to have already been preadapted to bind human sialoglycans.

Plasmodium falciparum↗

PubMed2026

New insights on Plasmodium gene expression from direct RNA sequencing.

Oxford Nanopore Technology (ONT) direct RNA sequencing enables the sequencing of native RNA molecules without cDNA conversion. The long-read approach captures full-length reads spanning entire genes and has transformed the study of gene expression in Plasmodium parasites by enabling analysis of untranslated regions, isoforms, and alternative splicing. In addition, ONT provides unique insights into non-coding RNAs, RNA modifications, and polyadenylated tail dynamics, which are expanding our understanding of post-transcriptional regulation in Plasmodium, including processes beyond translational repression in gametocytes and sporozoites. Here, we discuss the past and future applications of direct RNA sequencing in Plasmodium research and highlight its advantages, limitations, and future prospects.

Oxford Nanopore Technology↗

PubMed2026

Plasmodium thiamine pyrophosphokinase is essential for sporozoite formation and activation of an antiplasmodial thiamine analogue.

Oxythiamine, a thiamine analogue, inhibits Plasmodium falciparum proliferation by acting as an antimetabolite of vitamin B1. To elucidate in more detail its underlying mechanism of action, in vitro drug pressure was employed to generate oxythiamine-resistant P. falciparum lines. Whole-genome sequencing revealed that resistance was conferred by a single-point mutation in the thiamine pyrophosphokinase (TPK) gene. The mutated TPK has reduced activity, thereby likely limiting the conversion of oxythiamine into its active toxic form. To investigate the functional role of TPK across the parasite life cycle, a TPK-knockout line was generated in Plasmodium berghei. TPK-knockout parasites displayed a minor fitness cost during intraerythrocytic proliferation that could be overcome by infecting reticulocytes, but their sensitivity to oxythiamine was reduced fivefold in vivo, consistent with the hypothesis that activation of oxythiamine via TPK is essential for its antiplasmodial activity. In the Anopheles vector, TPK-knockout parasites produced a similar number of oocysts as wild-type parasites, but oocyst maturation was impaired and sporozoite formation was completely inhibited. These findings underscore an essential role for TPK in mediating the antiplasmodial activity of oxythiamine and reveal its critical function in sporogony within the mosquito, supporting its potential as a transmission-blocking target for antimalarial intervention.

Animals↗

PubMed2026

Parasite clearance in patients with Plasmodium vivax monoinfection treated with artesunate in Cambodia: an observational secondary analysis of trial data.

BACKGROUND: Artemisinin-based combination therapies are the frontline drugs for the treatment of malaria infections, but, for Plasmodium falciparum, the efficacy of artemisinin is threatened by the spread of resistance. Plasmodium vivax is the second most common cause of human malaria, but there is little information on its susceptibility to artemisinin due to the lack of an in-vitro culture system. This study aims to characterise the response of P vivax to artesunate using clinical, genomic, and transcriptomic data from infected individuals in Cambodia. METHODS: We analysed 161 P vivax infections from 87 patients (six female and 81 male; median age 20 years [IQR 17-26]) enrolled between Nov 10, 2021, and Nov 18, 2022, in a drug efficacy study in Cambodia and treated with 2 mg/kg/day of artesunate for 7 days. To determine clearance rates, we measured parasitaemia before, and 1 h, 2 h, 4 h, 8 h, and 16 h after the first dose of artesunate, and then at 24-h intervals during the 7 days of artesunate therapy. We also examined the parasites' genome sequences and used RNA sequencing of 31 infections to analyse changes in parasite gene expression upon treatment. FINDINGS: All infections were successfully cleared by day 3. However, 49 of the infections displayed a slow clearance after treatment, including nine (6%) infections with a parasite clearance slope half-life greater than 5 h. We observed no significant association between slow clearance and either patient or infection characteristics (including the infection's stage composition). Analyses of gene expression showed that, while fast-clearing parasites displayed significant changes in gene expression immediately upon treatment, slow-clearing parasites had a delayed gene expression response characterised notably by a downregulation of genes associated with haemoglobin endocytosis and digestion. INTERPRETATION: Some Cambodian P vivax parasites clear slowly after artesunate treatment, possibly due to a downregulation of haemoglobin metabolism that might reduce the efficiency of the artesunate. The slow clearance could allow parasites to outlast artesunate treatment and facilitate emergence of resistance to the artemisinin-combination therapy partner drug, threatening malaria elimination effort. FUNDING: US National Institutes of Health.

Adolescent↗

PubMed2002

A multigene family that interacts with the amino terminus of plasmodium MSP-1 identified using the yeast two-hybrid system.

Merozoite surface protein 1 (MSP-1) is a high-molecular-weight protein expressed on the surface of the malaria merozoite in a noncovalent complex with other protein molecules. MSP-1 undergoes a series of proteolytic processing events, but no precise biological role for the various proteolytic fragments of MSP-1 or for the additional proteins present in the complex is known. Through the use of the yeast two-hybrid system, we have isolated genes encoding proteins that interact with a region of the amino-terminal proteolytic fragment of MSP-1 from the mouse parasite Plasmodium yoelii. This analysis has led to the isolation of two sequence-related molecules, one of which is the P. yoelii homologue of MSP-7 originally described in Plasmodium falciparum. BLAST analysis of the P. falciparum database has revealed that there are six related protein molecules present in this species encoded near each other on chromosome 13. In P. falciparum, we designated these molecules MSRP-1 to -5. Analysis of the P. yoelii database indicates a similar chromosomal organization for the two genes in the mouse parasite species. The three P. falciparum sequences with the highest degree of homology to the P. yoelii sequences isolated in the two-hybrid screen have been characterized at the molecular level (MSRP-1 to -3). Expression analysis indicated that the mRNAs are expressed at various levels in the different asexual stages. Immunofluorescence studies colocalized the expression of the MSRP molecules and the amino-terminal portion of MSP-1 to the surfaces of trophozoites. In vitro binding experiments confirmed the interaction between MSRP-1, MSRP-2, and the amino-terminal region of P. falciparum MSP-1.

Amino Acid Sequence↗

PubMed2025

Degradation of ribosomal RNA during Plasmodium falciparum gametocytogenesis.

The life cycle of Plasmodium falciparum is characterized by complex regulatory changes that allow adaptation of the parasites to different environmental conditions, which are especially pronounced during transmission between the mammalian host and the insect vector. Previous studies have shown that P. falciparum uses three types of ribosomal RNAs (rRNA A, S1, and S2 types) at different stages of its life cycle. We used Oxford Nanopore Technologies direct RNA sequencing to investigate the dynamics of rRNA usage throughout the parasite's intraerythrocytic development, as well as in salivary gland sporozoites. Our study revealed a preponderance of A-type rRNAs during the intraerythrocytic cycle and gametocytogenesis, while S-type rRNAs slowly increase in abundance in mosquito stages starting 3 days post-infection. Salivary gland sporozoites showed an even proportion of all rRNA types. By examining the length distributions of rRNA molecules, we detected an extensive and specific degradation of rRNAs during gametocytogenesis, starting in stage II gametocytes and continuing until the final stages of gametocyte development. We hypothesize that rRNA degradation may be linked to the global translational repression and metabolic quiescence described in stage V gametocytes, similar to mechanisms observed in bacterial and eukaryotic stress responses.IMPORTANCEOur study uses Oxford Nanopore direct RNA sequencing of tightly synchronized blood-stage Plasmodium falciparum parasites to investigate the expression of ribosomal RNAs during asexual and sexual development. P. falciparum utilizes distinct types of rRNA during its development. However, due to the challenges of differentiating these highly similar molecules, their regulation and the mechanism underlying the switch between rRNA types remain unclear. We observe significant rRNA degradation in mature gametocytes, leading us to propose that this potentially leads to a reduced number of functional ribosomes when parasites become quiescent and translation is repressed.

Plasmodium falciparum↗

PubMed2025

Acetyl-CoA synthetase mutations affect the susceptibility of Plasmodium falciparum to antimalarial drugs.

Plasmodium falciparum acetyl-CoA synthetase (PfAcAS) is an important source of acetyl-CoA. We detected mutations S868G and V950I in PfAcAS by whole-genome sequencing analysis in certain recrudescent parasites after treatment with artesunate and dihydroartemisinin-piperaquine. Using CRISPR/Cas9 technology, we engineered parasite lines to carry the PfAcAS S868G and V950I mutations in two genetic backgrounds and evaluated their susceptibilities to antimalarial drugs in vitro. The results demonstrated that PfAcAS S868G and V950I mutations alone or in combination affected the susceptibility of P. falciparum to several antimalarial drugs, including the artemisinin derivatives (dihydroartemisinin, artesunate, and artemether) and chloroquine, although absolute changes in susceptibilities were modest.IMPORTANCEMalaria, an infectious disease caused by Plasmodium parasites and transmitted by mosquitoes, continues to be one of the most pressing public health challenges worldwide. P. falciparum has demonstrated reduced sensitivity to artemisinin-based combination therapies (ACTs), thereby intensifying the difficulties associated with malaria management. Currently, only a limited number of molecular markers exist for identifying drug resistance in P. falciparum, and these markers do not fully elucidate the mechanisms behind this resistance. In this study, we performed whole-genome sequencing analysis on P. falciparum strains that reemerged following ACT treatment. We aim to identify molecules potentially associated with drug resistance, which may provide new molecular markers for monitoring drug resistance in P. falciparum.

Plasmodium falciparum↗

PubMed2026

Population genomics of Plasmodium malariae from 4 African countries.

BACKGROUNDMalaria caused by Plasmodium malariae is geographically widespread and sometimes associated with prolonged infection, yet little is known about its genomic epidemiology.METHODSWe performed hybrid capture and whole-genome sequencing of 77 isolates collected from Cameroon (n = 7), the Democratic Republic of the Congo (n = 16), Nigeria (n = 4), and Tanzania (n = 50) between 2015 and 2021, analyzing parasite genetic population structure and demography.RESULTSThere is no evidence of geographic population structure. Nucleotide diversity was significantly lower than in colocalized P. falciparum isolates, while linkage disequilibrium was significantly higher. Genome-wide selection scans identified no erythrocyte invasion ligands or antimalarial resistance orthologs as top hits; however, targeted analyses of these loci revealed evidence of selective sweeps around 4 erythrocyte invasion ligands and 6 antimalarial resistance orthologs. Demographic inference modeling suggests that African P. malariae is recovering from a bottleneck.CONCLUSIONP. malariae is genomically atypical among human Plasmodium spp. and lacks strong population structure in Africa. The low diversity has potential impacts on understanding persistent versus new infection through genomic epidemiology.FUNDINGBill & Melinda Gates Foundation (grant 002202), USAID/PMI through Jhpiego and CDC, NIH (T32AI007151, T32AI070114, R01AI107949, R01AI129812, R21 AI148579, R01AI137395, R21AI152260, R01AI132547, and K24AI134990), and the DELTAS Africa initiative (DELGEME grant 107740/Z/15/Z).

Plasmodium malariae↗

PubMed2026

Plasmodium knowlesi can adapt to infect Duffy-negative erythrocytes.

Plasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Similar to its close relative Plasmodium vivax, P knowlesi relies on the Duffy antigen receptor for chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we demonstrate that P knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate within Duffy-negative (Fy-) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy- erythrocytes and to resist inhibition by α-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbpα and dbpγ genes, resulting in a new chimeric gene dbpαγ. Using CRISPR-Cas9 targeted reversion, we could demonstrate that dbpαγ is essential for invasion of Fy- erythrocytes. These findings shed new light on the invasion plasticity of P knowlesi, with implications for the parasite's potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P vivax.

Plasmodium knowlesi↗

PubMed2026

Genetic diversity of Plasmodium falciparum helical interspersed subtelomeric (phistb) gene in Tanzania and neighboring countries.

BACKGROUND: Lysine-rich membrane associated Plasmodium helical interspersed subtelomeric gene (phistb) is a member of the phist family of genes which encodes exported proteins essential for the parasite's survival within infected red blood cells. Recent studies suggest the phistb gene as a promising malaria vaccine candidate, however, its genetic diversity remains understudied. This study assessed the genetic diversity of the phistb gene in regions of varying malaria transmission aiming to generate data and improve our understanding of this promising malaria vaccine candidate gene. METHODS: Genomic data from 1472 Plasmodium falciparum samples from Tanzania, Kenya, Uganda, and Ethiopia were retrieved in variant Calling file format (VCF) format from the MalariaGEN Pf7 database. Variants were filtered to include only biallelic Single Nucleotide Polymorphism (SNPs) with Variant Quality Score Log- Odds (VQSLOD) > 1 and "PASS" status. Genetic diversity, differentiation, and selection signatures were analyzed using population genetics metrics. RESULTS: After filtering, 1312 samples were retained. Wright's inbreeding coefficient (Fws) showed that 875 (66.7%) samples had monoclonal infections, with the highest proportion of monoclonal infections in Ethiopia (95.3%), followed by Tanzania (67.2%), Kenya (65.7%), and Uganda (50%). Among the 875 monoclonal samples, 88 haplotypes were identified, with Hap_1 (renamed PF3D7) and Hap_13 comprising 37.9 and 21.5 of the samples, respectively. Nucleotide and haplotype diversity were relatively higher in Kenya with 0.097, and 0.88 respectively, compared to the other study populations. The overall fixation index (Fst) was < 0.05, and Principal Component Analysis revealed no clear population sub-structure among countries. Negative Tajima's D values in Tanzania, Kenya, and Ethiopia indicated an excess of low-frequency alleles. CONCLUSION: This study reports low genetic diversity of the phistb gene in the four countries despite varying malaria transmission intensities among them, thus making it a suitable candidate gene for malaria vaccine. Further studies should be conducted to assess individual antibodies recognition of the phistb variants and the ability to elicit cross reactivity to further support its potential as a vaccine candidate.

Plasmodium falciparum↗

PubMed2025

Widespread release of translational repression across Plasmodium's host-to-vector transmission event.

Malaria parasites must respond quickly to environmental changes, including during their transmission between mammalian and mosquito hosts. Therefore, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. While the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, changes in the spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known. Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics of Plasmodium parasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes of P. yoelii, we found that ~200 transcripts are released for translation soon after fertilization, including those encoding essential functions. Moreover, we identified that many transcripts remain repressed beyond this point. TurboID-based proximity proteomics of the DOZI/CITH/ALBA regulatory complex revealed substantial spatial and/or compositional changes across this transmission event, which are consistent with recent, paradigm-shifting models of translational control. Together, these data provide a model for the essential translational control mechanisms that promote Plasmodium's efficient transmission from mammalian host to mosquito vector.

Animals↗

PubMed2025

Plasmodium ARK1 regulates spindle formation during atypical mitosis and forms a divergent chromosomal passenger complex.

Mitosis in Plasmodium spp., the causative agent of malaria, is fundamentally different from model eukaryotes, proceeding via a bipartite microtubule organising centre (MTOC) and lacking canonical regulators such as Polo and Bub1 kinases. During schizogony, asynchronous nuclear replication produces a multinucleate schizont, while rapid male gametogony generates an octaploid nucleus before gamete formation. Here, we identify Aurora-related kinase 1 (ARK1) as a key component of inner MTOC and spindle formation, controlling kinetochore dynamics and driving mitotic progression. Conditional ARK1 depletion disrupts spindle biogenesis, kinetochore segregation, karyokinesis and cytokinesis in both stages, and affects parasite transmission. Interactome analysis reveals ARK1 as the catalytic core of a non-canonical chromosomal passenger complex (CPC) containing two divergent inner centromere proteins (INCENPs) but lacking Survivin and Borealin. Comparative genomics indicates this CPC architecture arose early in Apicomplexa, replacing canonical centromere-targeting modules. These findings uncover a distinct mitotic machinery in Plasmodium and identify the ARK1-INCENP interface as a potential multistage target for malaria therapeutic intervention.

Aurora kinase↗

PubMed2024

NAD activates olfactory receptor 1386 to regulate type I interferon responses in Plasmodium yoelii YM infection.

Olfactory receptors (Olfr) are G protein-coupled receptors that are normally expressed on olfactory sensory neurons to detect volatile chemicals or odorants. Interestingly, many Olfrs are also expressed in diverse tissues and function in cell-cell recognition, migration, and proliferation as well as immune responses and disease processes. Here, we showed that many Olfr genes were expressed in the mouse spleen, linked to Plasmodium yoelii genetic loci significantly, and/or had genome-wide patterns of LOD scores (GPLSs) similar to those of host Toll-like receptor genes. Expression of specific Olfr genes such as Olfr1386 in HEK293T cells significantly increased luciferase signals driven by IFN-β and NF-κB promoters, with elevated levels of phosphorylated TBK1, IRF3, P38, and JNK. Mice without Olfr1386 were generated using the CRISPR/Cas9 method, and the Olfr1386-/- mice showed significantly lower IFN-α/β levels and longer survival than wild-type (WT) littermates after infection with P. yoelii YM parasites. Inhibition of G protein signaling and P38 activity could affect cyclic AMP-responsive element promoter-driven luciferase signals and IFN-β mRNA levels in HEK293T cells expressing the Olfr1386 gene, respectively. Screening of malaria parasite metabolites identified nicotinamide adenine dinucleotide (NAD) as a potential ligand for Olfr1386, and NAD could stimulate IFN-β responses and phosphorylation of TBK1 and STAT1/2 in RAW264.7 cells. Additionally, parasite RNA (pRNA) could significantly increase Olfr1386 mRNA levels. This study links multiple Olfrs to host immune response pathways, identifies a candidate ligand for Olfr1386, and demonstrates the important roles of Olfr1386 in regulating type I interferon (IFN-I) responses during malaria parasite infections.

Animals↗

PubMed2026

Signal recognition particle 14 binds to importin α in Plasmodium falciparum.

BACKGROUND: The eukaryotic signal recognition particle (SRP) consists of six proteins and one SRP RNA. This ribonucleoprotein complex assembles inside the nucleus. Nucleocytoplasmic transport is an essential process for the biogenesis of signal recognition particles (SRPs) as well as for the survival of a cell. There are studies on cells that indicate the import receptor is responsible for import of SRP proteins into nucleus, but there is a lack of evidence that SRP proteins directly bind with import receptors. METHODS AND RESULTS: Coding sequences of SRP 14 and importin α were amplified from synthesized cDNA and genomic DNA, respectively, of Plasmodium falciparum cultivated in vitro culture. The amplified products were cloned and expressed in E. coli, followed by purification. A binding study was conducted on glutathione-agarose as well as in a 96-well plate format at different concentrations of SRP 14 with immobilized importin α. CONCLUSION: This is the first report of direct binding between importin α and a eukaryotic signal recognition particle 14 (SRP 14). A cost-effective 96-well plate-based assay has also been developed to study the binding of cargoes of importin α.

Plasmodium falciparum↗

PubMed2008

Isolation and characterization of Plasmodium falciparum UAP56 homolog: evidence for the coupling of RNA binding and splicing activity by site-directed mutations.

UAP56 (U2AF65 associated protein) is a member of the DEAD-box helicase family. Helicases are essential enzymes generally involved in the metabolism of nucleic acids. The gene encoding a member of DEAD-box family was cloned and characterized from the human malaria parasite Plasmodium falciparum. PfU52 is homologous to UAP56 and contains the RNA-dependent ATPase, RNA helicase and RNA binding activities. Using the parasite extract we report that PfU52 is involved in splicing reaction. Site-directed mutagenesis studies indicate that the conserved residues glycine 181, isoleucine 182 and arginine 206 are involved in RNA binding and this activity is required for the enzymatic activities of PfU52. PfU52 is expressed in all the intraerythrocytic developmental stages of the parasite. In the present study we have reported the detailed characterization of PfU52 from P. falciparum and these results advance the knowledge regarding the function of UAP56 in general.

Adenosine Triphosphatases↗

PubMed2026

Genetic polymorphism in Plasmodium falciparum MSPDBL1 and MSPDBL2 and their impact on B- and T-cell immunodominant epitopes in Brazilian malaria-endemic areas.

Merozoite Surface Protein Duffy Binding-like 1 and 2 (MSPDBL1 and MSPDBL2) are involved in erythrocyte invasion by Plasmodium falciparum. Antibodies targeting PfMSPDBL1 and PfMSPDBL2 show strong opsonizing and growth-inhibitory activities, supporting their potential as asexual blood-stage vaccine candidates. Given that the extensive genetic diversity of P. falciparum contributes to immune evasion, identifying polymorphisms in regions encoding PfMSPDBL1 and PfMSPDBL2 is essential to assess their relevance as vaccine targets. In this study, we investigated polymorphisms in the pfmspdbl1 and pfmspdbl2 genes and their impact on potentially antigenic regions within the Duffy Binding-like (DBL) and Secreted Polymorphic Antigen Associated with Merozoite (SPAM) domains. Blood samples were collected from 47 P falciparum-infected individuals from three malaria-endemic areas of the Brazilian Amazon. Genomic DNA was extracted, PCR-amplified, and sequenced. Intrapopulation genetic diversity and Tajima's D values were estimated using bioinformatics tools. Linear B- and T-cell epitopes were predicted using BCPreds and IEDB (Immune Epitope Database), respectively. Two and thirty-two polymorphisms were identified in pfmspdbl1 within the SPAM and DBL domains, respectively, whereas pfmspdbl2 presented two polymorphisms across both domains and a 12 bp insertion in the SPAM domain. Tajima's D values were positive across domains, except for the DBL domain of pfmspdbl2 in Mâncio Lima. Fifteen B-cell and fifteen T-cell epitopes were predicted, with polymorphisms in three B-cell epitopes affecting Vaxijen scores. Together, these findings reveal contrasting evolutionary patterns between PfMSPDBL1 and PfMSPDBL2, with potential implications for antigenicity, and highlight PfMSPDBL2 as a potential candidate for further evaluation in multicomponent blood-stage malaria vaccine development.

Genetic diversity↗

PubMed2026

Artemether-lumefantrine for the treatment of Plasmodium falciparum malaria in Laos: a therapeutic efficacy study coupled with genomic and in vitro phenotypic analyses.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have played a crucial role in decreasing the impact of malaria worldwide. Since 2005, artemether-lumefantrine (AL) has been the main first-line treatment for uncomplicated Plasmodium falciparum malaria in Laos. Herein, we aimed to study the efficacy of AL in the context of malaria elimination in Laos. METHODS: Between Aug 1, 2019, and June 11, 2023, AL efficacy was evaluated in four provinces of southern Laos: Attapeu, Champassack, Salavan, and Savannakhet. Adults and children (aged 1-60 years) with microscopically confirmed P falciparum malaria received oral AL twice a day for 3 days, with follow-up on days 7, 14, 21, and 28. The primary outcome was PCR-adjusted adequate clinical and parasitological response (ACPR) by day 28. Resistance to dihydroartemisinin (DHA) and lumefantrine (LM) was assessed by an in vitro phenotypic analysis, and mutations in P falciparum kelch13 (pfkelch13), P falciparum multidrug resistance 1 (pfmdr1), P falciparum plasmepsin 2 (pfpm2), and P falciparum chloroquine resistant transporter (pfcrt) were characterised in parasites collected from enrolled patients. Safety outcomes included the frequency and nature of adverse events and serious adverse events. FINDINGS: A total of 198 patients (median age 16 years [IQR 10-28]; 124 [63%] male and 74 [37%] female) were initially enrolled, of whom three were lost to follow-up, resulting in 195 patients who received the 3-day AL regimen. At day 28, the PCR-adjusted ACPR was 96% (95% CI 92-98), with a treatment failure rate of 2% (1-5) and a reinfection rate of 2% (1-5). Among the four PCR-confirmed recrudescent isolates, one showed markedly reduced LM susceptibility (LM 50% inhibitory concentration [IC50] 59·9 nM, 2·5 times higher than the median IC50 of other isolates) and high artemisinin resistance in vitro (ring-stage survival survival rate 35·8%), which was associated with the pfkelch13 R539T mutation and day-3 microscopy-positive parasitaemia. Among 190 isolates with successfully determined pfkelch13 sequencing, nine (5%) carried the pfkelch13 mutation R539T and 43 (23%) carried the C580Y mutation, and both were associated with day-3 microscopy-positive parasitaemia (p=0·044). No amplification of pfmdr1 or pfpm2, nor any mutations in pfmdr1 and pfcrt, were associated with treatment failure. INTERPRETATION: Our findings indicate the potential emergence of LM resistance in Laos. Although AL remains efficacious, vigilance for decreasing efficacy and close monitoring of LM efficacy should be considered to support the country's goal of eliminating malaria by 2030. Importantly, none of the known pfmdr1 or pfcrt haplotypes were uniquely associated with treatment failure, including the isolate with the highest LM IC50, underscoring the need to identify reliable molecular markers for LM resistance. FUNDING: Bill and Melinda Gates Foundation and The Global Fund.

Humans↗