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Annual Review of Microbiology Sep 2023Infections caused by malaria parasites place an enormous burden on the world's poorest communities. Breakthrough drugs with novel mechanisms of action are urgently... (Review)
Review
Infections caused by malaria parasites place an enormous burden on the world's poorest communities. Breakthrough drugs with novel mechanisms of action are urgently needed. As an organism that undergoes rapid growth and division, the malaria parasite is highly reliant on protein synthesis, which in turn requires aminoacyl-tRNA synthetases (aaRSs) to charge tRNAs with their corresponding amino acid. Protein translation is required at all stages of the parasite life cycle; thus, aaRS inhibitors have the potential for whole-of-life-cycle antimalarial activity. This review focuses on efforts to identify potent plasmodium-specific aaRS inhibitors using phenotypic screening, target validation, and structure-guided drug design. Recent work reveals that aaRSs are susceptible targets for a class of AMP-mimicking nucleoside sulfamates that target the enzymes via a novel reaction hijacking mechanism. This finding opens up the possibility of generating bespoke inhibitors of different aaRSs, providing new drug leads.
Topics: Humans; Antimalarials; Amino Acyl-tRNA Synthetases; Plasmodium falciparum; Malaria; RNA, Transfer
PubMed: 37018842
DOI: 10.1146/annurev-micro-032421-121210 -
The New England Journal of Medicine Sep 2023Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin...
BACKGROUND
Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in on the continent is troubling, given the lack of alternative treatments.
METHODS
In this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in as predictive markers of partial resistance to artemisinin and screened for deletions in and that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.
RESULTS
We noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both and were identified in 16.9% of the parasites that carried the R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.
CONCLUSIONS
The emergence and spread of lineages with both -mediated partial resistance to artemisinin and deletions in and in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.).
Topics: Humans; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Eritrea; Malaria, Falciparum; Plasmodium falciparum; Prevalence
PubMed: 37754284
DOI: 10.1056/NEJMoa2210956 -
Trends in Parasitology Nov 2023Nutrient import and waste efflux are critical dependencies for intracellular Plasmodium falciparum parasites. Nutrient transport proteins are often lineage specific and... (Review)
Review
Nutrient import and waste efflux are critical dependencies for intracellular Plasmodium falciparum parasites. Nutrient transport proteins are often lineage specific and can provide unique targets for antimalarial drug development. P. falciparum nutrient transport pathways can be a double-edged sword for the parasite, not only mediating the import of nutrients and excretion of waste products but also providing an access route for drugs. Here we briefly summarise the nutrient acquisition pathways of intracellular P. falciparum blood-stage parasites and then highlight how these pathways influence many aspects relevant to antimalarial drugs, resulting in complex and often underappreciated interdependencies.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Antimalarials; Biological Transport; Nutrients; Protozoan Proteins
PubMed: 37716852
DOI: 10.1016/j.pt.2023.08.008 -
Nature Microbiology Dec 2023Malaria results in over 600,000 deaths annually, with the highest burden of deaths in young children living in sub-Saharan Africa. Molecular surveillance can provide...
Malaria results in over 600,000 deaths annually, with the highest burden of deaths in young children living in sub-Saharan Africa. Molecular surveillance can provide important information for malaria control policies, including detection of antimalarial drug resistance. However, genome sequencing capacity in malaria-endemic countries is limited. We designed and implemented an end-to-end workflow to detect Plasmodium falciparum antimalarial resistance markers and diversity in the vaccine target circumsporozoite protein (csp) using nanopore sequencing in Ghana. We analysed 196 clinical samples and showed that our method is rapid, robust, accurate and straightforward to implement. Importantly, our method could be applied to dried blood spot samples, which are readily collected in endemic settings. We report that P. falciparum parasites in Ghana are mostly susceptible to chloroquine, with persistent sulfadoxine-pyrimethamine resistance and no evidence of artemisinin resistance. Multiple single nucleotide polymorphisms were identified in csp, but their significance is uncertain. Our study demonstrates the feasibility of nanopore sequencing for malaria genomic surveillance in endemic countries.
Topics: Child; Humans; Child, Preschool; Plasmodium falciparum; Ghana; Nanopore Sequencing; Antimalarials; Malaria; Malaria, Falciparum; Drug Resistance
PubMed: 37996707
DOI: 10.1038/s41564-023-01516-6 -
Blood Dec 2023
Topics: Animals; Plasmodium falciparum; Membrane Proteins; Parasites; Erythrocyte Membrane; Erythrocytes
PubMed: 38060273
DOI: 10.1182/blood.2023022781 -
Innate Immunity Jul 2023Malaria is often characterized by a complicated disease course due to multifaceted intrinsic genetic factors of the host and the parasite. This study aimed to...
Malaria is often characterized by a complicated disease course due to multifaceted intrinsic genetic factors of the host and the parasite. This study aimed to investigate the role of interleukin-27 () gene polymorphisms in malaria infection in a Saudi Arabian cohort. This case-control study obtained blood samples from 250 malaria patients with and 200 randomly identified healthy control subjects from the Malaria Center in the Jazan area. Malaria patients were grouped into three cohorts as follow: low (<500 parasites/µl of blood), moderate (500-1000 parasites/µl of blood), and high (>1000 parasites/µl of blood) parasitemia. The results show that the IL-27 variant rs181209 was significantly associated with malaria patients ( = 0.026). Similarly, the homozygous GG genotype of rs26528 was also associated with risk of developing malaria ( = 0.032). The minor allele C of variant rs181206 exhibited an association with low to moderate parasitemia ( = 0.046). Furthermore, the rs181209 AA genotype was statistically significant in age group 1-5 years ( = 0.049). In conclusion, this study suggests that variant rs181209 and rs26528 could be associated with the risk of malaria infection by in the population studied.
Topics: Humans; Infant; Child, Preschool; Interleukin-27; Plasmodium falciparum; Parasitemia; Case-Control Studies; Saudi Arabia; Malaria, Falciparum; Malaria; Polymorphism, Genetic
PubMed: 37306242
DOI: 10.1177/17534259231178594 -
American Journal of Hematology Oct 2023Sickle cell disease (SCD) remains prevalent because heterozygous carriers (HbAS) are partially resistant to Plasmodium falciparum malaria. Sickle hemoglobin (HbS)...
BACKGROUND
Sickle cell disease (SCD) remains prevalent because heterozygous carriers (HbAS) are partially resistant to Plasmodium falciparum malaria. Sickle hemoglobin (HbS) polymerization in low and intermediate oxygen (O ) conditions is the main driver of HbAS-driven resistance to P. falciparum malaria. However, epidemiological studies have reported mixed malaria morbidity and mortality outcomes in individuals with sickle cell disease (SCD). While maximum-tolerated dose hydroxyurea has been shown to lower malaria incidence, fetal hemoglobin (HbF), an inhibitor of HbS polymerization that is variably packaged in F-erythrocytes, might provide hemoglobin that is accessible to the parasite for feeding.
METHODS
To explore that risk, we examined the effect of variable mean corpuscular fetal hemoglobin (MCHF) on P. falciparum proliferation, invasion, and development in HbSS RBCs.
RESULTS
We found that greater MCHF in HbSS red blood cells (RBCs) is associated with increased P. falciparum proliferation in O environments comparable with the microcirculation. Moreover, both parasite invasion and intracellular growth, the major components of proliferation, occur predominantly in F-erythrocytes and are augmented with increasing MCHF.
CONCLUSIONS
HbF modifies P. falciparum infection in HbSS RBCs, further highlighting the complexity of the molecular interactions between these two diseases. Other inhibitors of HbS polymerization that do not increase HbF or F-erythrocytes should be independently assessed for their effects on P. falciparum malaria proliferation in HbSS RBCs.
Topics: Humans; Anemia, Sickle Cell; Plasmodium falciparum; Malaria, Falciparum; Fetal Hemoglobin; Cell Proliferation; Erythrocytes
PubMed: 37584425
DOI: 10.1002/ajh.27042 -
ELife Dec 2023Apicomplexan parasites exhibit tremendous diversity in much of their fundamental cell biology, but study of these organisms using light microscopy is often hindered by...
Apicomplexan parasites exhibit tremendous diversity in much of their fundamental cell biology, but study of these organisms using light microscopy is often hindered by their small size. Ultrastructural expansion microscopy (U-ExM) is a microscopy preparation method that physically expands the sample by ~4.5×. Here, we apply U-ExM to the human malaria parasite during the asexual blood stage of its lifecycle to understand how this parasite is organized in three dimensions. Using a combination of dye-conjugated reagents and immunostaining, we have cataloged 13 different structures or organelles across the intraerythrocytic development of this parasite and made multiple observations about fundamental parasite cell biology. We describe that the outer centriolar plaque and its associated proteins anchor the nucleus to the parasite plasma membrane during mitosis. Furthermore, the rhoptries, Golgi, basal complex, and inner membrane complex, which form around this anchoring site while nuclei are still dividing, are concurrently segregated and maintain an association to the outer centriolar plaque until the start of segmentation. We also show that the mitochondrion and apicoplast undergo sequential fission events while maintaining an association with the outer centriolar plaque during cytokinesis. Collectively, this study represents the most detailed ultrastructural analysis of during its intraerythrocytic development to date and sheds light on multiple poorly understood aspects of its organelle biogenesis and fundamental cell biology.
Topics: Humans; Plasmodium falciparum; Microscopy; Ascomycota; Malaria, Falciparum; Apicoplasts; Plaque, Amyloid
PubMed: 38108809
DOI: 10.7554/eLife.88088 -
Journal of Korean Medical Science Jun 2024Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the...
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Topics: Humans; Malaria, Falciparum; Ghana; Antimalarials; Middle Aged; Male; Plasmodium falciparum; Proguanil; Atovaquone; Travel; Artemisinins; Artesunate; Parasitemia; Doxycycline; Drug Combinations; Treatment Failure; Artemether, Lumefantrine Drug Combination
PubMed: 38859743
DOI: 10.3346/jkms.2024.39.e186 -
Proceedings of the National Academy of... Jul 2023To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we...
To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.
Topics: Animals; Humans; Antimalarials; Adenosine Triphosphatases; Vacuoles; Malaria, Falciparum; Plasmodium falciparum; Parasites
PubMed: 37463201
DOI: 10.1073/pnas.2306420120