Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea
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ABSTRACT:
PROVIDER: PRJEB81824 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13911400_1.fastq.gz | Fastqsanger.gz | |||
| ERR13911400_2.fastq.gz | Fastqsanger.gz | |||
| ERR13911500_1.fastq.gz | Fastqsanger.gz | |||
| ERR13911500_2.fastq.gz | Fastqsanger.gz | |||
| ERR13911600_1.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn 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 P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.ResultsWe 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 Pfkelch13 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 Pfkelch13 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 Pfkelch13 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 hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 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.).
| S-EPMC10539021 | biostudies-literature
Project description:Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits. 91 malaria parasite isolates assayed for single nucleotide polymorphisms across 45K loci
2012-04-30 | E-GEOD-33002 | biostudies-arrayexpress
Project description:Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits.
2012-05-01 | GSE33002 | GEO
Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum infection associated with high mortality rates predominantly in children that live in sub-Saharan Africa. Histine rich protein 2 (HRP2) is a diagnostic and prognostic marker that can be detected in peripheral blood, cerebrospinal fluid and cord blood. Recent studies confirm that HRP2 crossess the compromised blood brain barrier (BBB) during HCM and infiltrate brain parenchyma. Treatments with HRP2 in murine experimental cerebral malaria (ECM) model recapitulate these effects. We tested the hypothesis that treatment of induced pluripotent stem cells (iPSC)-derived brain cortical organoids with HRP2 will recapitulate the brain effects. We assessed the effects of HRP2 treatment on ultrastructure, expression of markers of viability and inflammation neurons, astrocytes and microglia in organoids. We tested the neuroprotective effects of Neuregulin 1 (NRG1) against the HRP2 treatment. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.
2021-12-01 | GSE172366 | GEO
Project description:Human cerebral malaria (HCM) is a severe complication of Plasmodium falciparum (P.f.) infection that is characterized by capillary occlusions, rupture of the blood-brain barrier (BBB) and perivascular cellular injury. P.f. histidine-rich protein 2 (HRP2), a byproduct of parasitized red blood cell (pRBC) lysis, crosses the BBB when compromised to cause brain injury. We hypothesized that HRP2-induced neuronal damage can be attenuated by Neuregulin 1 (NRG1), an anti-inflammatory neuroprotective factor. Using brain cortical organoids, we determined that HRP2 upregulated cell death and inflammatory markers and disorganized brain organoid tissue. We identified Toll Like Receptors (TLR1 and 2) as potential mediators of HRP2-induced cellular damage and inflammation. Exogenous treatment of organoids with NRG1 attenuated HRP2 effects. The results indicate that HRP2 mediates malaria-associated HRP2-induced brain injury and inflammation and that NRG1 may be an effective therapy against HRP2 effects in the brain. In the study presented here, we assessed the inflammatory genes induced by HRP2 using the Immunology Panel on the nCounter system (NanoString) and results were analyzed using nSolver softaware.
2022-06-08 | GSE190750 | GEO
Project description:Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that HRP2-DPF3a-BAF complex coordinates histone H3 lysine 36 methylation (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamic and gene transcription during myogenic differentiation. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with BRG1/BRM associated factor (BAF) chromatin remodeling complex by direct interaction with BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex.
2020-05-13 | GSE148296 | GEO
Project description:Malaria-parasite survival of host fever is linked to artemisinin resistance
| PRJNA737104 | ENA
Project description:Plasmodium falciparum, the most pathogenic human malaria parasite, infects millions of human beings and causes a serious public health threat. Currently, the most potent anti-malarial drugs are artemisinin and its derivatives1,2. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge3. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources4. Once activated, artemisinins are converted into highly reactive carbon-centered radicals5,6 that attack macromolecules through alkylation and propagate a series of damages, eventually leading to parasite death7,8. Even though several parasite proteins have been reported as the targets of artemisinin9,10, the exact mechanism of artemisinin action is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted. Here, we have developed an unbiased chemical proteomics approach to directly probe the mechanism of action of artemisinin in P. falciparum in situ. An alkyne-tagged artemisinin analogue coupled with biotin enables selective purification and identification of 124 artemisinin covalent-binding protein targets, many of which are involved in essential biological processes of the parasite. In vitro assays confirm the specific artemisinin binding and inhibition of selected targets. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. Furthermore, using the alkyne-tagged artemisinin coupled with a fluorescent dye to monitor its protein binding, we showed that heme, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The extremely high level of heme released from the hemoglobin digestion by the parasite make artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages) compared to parasites at early ring stage, which have low level of heme, mainly from endogenous synthesis. The ‘blood eating’ nature of the parasite with the release of large amounts of heme confers artemisinin with extremely high specificity against the parasites, with minimum side effects towards healthy red blood cells. Taken together, our results established a unifying model to explain the action and specificity of artemisinin in parasite killing. Our findings could facilitate the development of better alternative strategies to treat malaria in times of emerging artemisinin resistance11,12.
2015-12-17 | PXD002611 | Pride
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation.
2010-12-07 | GSE25879 | GEO
Project description:Artemisinin resistance in Plasmodium falciparum malaria has emerged in western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. Using DNA microarrays we identify key features of a transcriptional profile that are associated with the delayed parasite clearance phenotype. These include reduced expression of several basic metabolic and cellular pathways in the early stages, and increased expression of essentially all functionalities associated with protein metabolism in the later stages of P. falciparum intraerythrocytic development. This is consistent with the reduced ring stage susceptibility that characterizes artemisinin resistant P. falciparum. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of several regulatory proteins such as transcription factors of chromatin remodeling associated factors. In addition, the artemisinin resistant phenotype is strongly associated with a specific pattern of copy number variations, some of which are linked with differential expression of several regulatory proteins such as histone 4 and zinc permease. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides a set of candidate genes for further investigation.
2010-12-07 | GSE25878 | GEO