Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa
. Here we ...genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance
, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda
. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.
In the version of this article initially published, affiliation 2 (Malaria Genetics and Resistance Unit, Institut Pasteur, Paris, France) was incorrect. The correct affiliation is ‘Malaria Genetics ...and Resistance Unit–Institut Pasteur, INSERM U1201, CNRS ERL9195, Paris, France’. Also, in the first sentence in the first paragraph of the fifth subsection of Results (‘Origins of the Rwandan Pfkelch13 561H haplotype and its relationship to other P. falciparum populations’), the first part of the sample description (“350 samples, comprising 25 Rwandan sequences and 10 Eritrean P. falciparum sequences generated for this study”) was incorrect. The correct text is “...340 samples, comprising 25 Rwandan P. falciparum sequences generated for this study...”. Finally, Fig. 1 was incorrect, and the number of worldwide isolates in the legend title (325) was incorrect. The corrected figure is presented here, and the correct number of worldwide isolates is 315. The errors have been corrected in the HTML and PDF versions of the article
Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a ...molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia ...and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure.
Artemisinin is currently the most widely used and effective compound against malaria parasites and it plays a critical role in treatment and ongoing control efforts of malaria worldwide.Unfortunately, emergence of resistance to artemisinin has occurred in Southeast Asia and was shown to be associated with mutations in the K13 gene.Artemisinin kills parasites by increasing oxidative stress in the infected red blood cell, leading to an increased level of unfolded protein.The unfolded protein response of the parasite is associated with a PK4/EIf2a response that can lead to parasite latency. K13 mutations are thought to alter ubiquitination patterns and help parasites to resist the accumulation of polyubiquinated proteins. How these two pathways interplay is not fully understood.Recombinant parasite and single-cell technologies provide powerful avenues to decipher the mode of action of artemisinin and the function of K13.
The mite Sarcoptes scabiei is responsible for scabies, a pruritic and contagious skin disease in humans. S. scabiei is also responsible for mange in a wide range of animal species. The treatment of ...S. scabiei infection is hampered by an under-effectiveness of the few available drugs. The objective of this work was to evaluate the in vitro acaricide activity of a large number of plant essential oils (EOs) against S. scabiei. EOs were selected mainly on the basis of traditional treatments for dermatological infections in Madagascar. The sarcoptes originating from a porcine animal model were tested at concentrations ranging from 10 to 0.1%. The viability of sarcoptes was assessed by stereomicroscopic observation at 5 min, 15 min, 30 min, 45 min and then every hour until 6 h after treatment. Estimates of lethal time and lethal concentration producing 50% mortality were generated using a probit analysis. The survival curves were estimated using the Kaplan Meier method. A total of 31 EOs from different plants were tested. Cinnamomum zeylanicum (cinnamom) and Ocimum sanctum (tulsi) oils were the most active for all concentrations tested. They may be included in in vivo studies, in order to further assess their potential interest as topical treatments.
Abstract
Toxoplasma gondii
is a cyst-forming apicomplexan parasite of virtually all warm-blooded species, with all true cats (Felidae) as definitive hosts. It is the etiologic agent of toxoplasmosis, ...a disease causing substantial public health burden worldwide. Few intercontinental clonal lineages represent the large majority of isolates worldwide. Little is known about the evolutionary forces driving the success of these lineages, the timing and the mechanisms of their global dispersal. In this study, we analyse a set of 156 genomes and we provide estimates of
T. gondii
mutation rate and generation time. We elucidate how the evolution of
T. gondii
populations is intimately linked to the major events that have punctuated the recent history of cats. We show that a unique haplotype, whose length represents only 0.16% of the whole
T. gondii
genome, is common to all intercontinental lineages and hybrid populations derived from these lineages. This haplotype has accompanied wildcats (
Felis silvestris
) during their emergence from the wild to domestic settlements, their dispersal in the Old World, and their expansion in the last five centuries to the Americas. The selection of this haplotype is most parsimoniously explained by its role in sexual reproduction of
T. gondii
in domestic cats.
The declining efficacy of dihydroartemisinin-piperaquine against Plasmodium falciparum in Cambodia, along with increasing numbers of recrudescent cases, suggests resistance to both artemisinin and ...piperaquine. Available in vitro piperaquine susceptibility assays do not correlate with treatment outcome. A novel assay using a pharmacologically relevant piperaquine dose/time exposure was designed and its relevance explored in retrospective and prospective studies.
The piperaquine survival assay (PSA) exposed parasites to 200 nM piperaquine for 48 hours and monitored survival 24 hours later. The retrospective study tested 32 culture-adapted, C580Y-K13 mutant parasites collected at enrolment from patients treated with a 3-day course of dihydroartemisinin-piperaquine and having presented or not with a recrudescence at day 42 (registered ACTRN12615000793516). The prospective study assessed ex vivo PSA survival rate alongside K13 polymorphism of isolates collected from patients enrolled in an open-label study with dihydroartemisinin-piperaquine for uncomplicated P. falciparum malaria in Cambodia (registered ACTRN12615000696594).
All parasites from recrudescent cases had in vitro or ex vivo PSA survival rates ≥10%, a relevant cut-off value for piperaquine-resistance. Ex vivo PSA survival rates were higher for recrudescent than non-recrudescent cases (39.2% vs. 0.17%, P <1 × 10(-7)). Artemisinin-resistant K13 mutants with ex vivo PSA survival rates ≥10% were associated with 32-fold higher risk of recrudescence (95% CI, 4.5-224; P = 0.0005).
PSA adequately captures the piperaquine resistance/recrudescence phenotype, a mainstay to identify molecular marker(s) and evaluate efficacy of alternative drugs. Combined ex vivo PSA and K13 genotyping provides a convenient monitor for both artemisinin and piperaquine resistance where dihydroartemisinin-piperaquine is used.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Resistance to anti-malarial drugs hampers control efforts and increases the risk of morbidity and mortality from malaria. The efficacy of standard therapies for uncomplicated Plasmodium falciparum ...and Plasmodium vivax malaria was assessed in Chumkiri, Kampot Province, Cambodia.
One hundred fifty-one subjects with uncomplicated falciparum malaria received directly observed therapy with 12 mg/kg artesunate (over three days) and 25 mg/kg mefloquine, up to a maximum dose of 600 mg artesunate/1,000 mg mefloquine. One hundred nine subjects with uncomplicated vivax malaria received a total of 25 mg/kg chloroquine, up to a maximum dose of 1,500 mg, over three days. Subjects were followed for 42 days or until recurrent parasitaemia was observed. For P. falciparum infected subjects, PCR genotyping of msp1, msp2, and glurp was used to distinguish treatment failures from new infections. Treatment failure rates at days 28 and 42 were analyzed using both per protocol and Kaplan-Meier survival analysis. Real Time PCR was used to measure the copy number of the pfmdr1 gene and standard 48-hour isotopic hypoxanthine incorporation assays were used to measure IC50 for anti-malarial drugs.
Among P. falciparum infected subjects, 47.0% were still parasitemic on day 2 and 11.3% on day 3. The PCR corrected treatment failure rates determined by survival analysis at 28 and 42 days were 13.1% and 18.8%, respectively. Treatment failure was associated with increased pfmdr1 copy number, higher initial parasitaemia, higher mefloquine IC50, and longer time to parasite clearance. One P. falciparum isolate, from a treatment failure, had markedly elevated IC50 for both mefloquine (130 nM) and artesunate (6.7 nM). Among P. vivax infected subjects, 42.1% suffered recurrent P. vivax parasitaemia. None acquired new P. falciparum infection.
The results suggest that artesunate-mefloquine combination therapy is beginning to fail in southern Cambodia and that resistance is not confined to the provinces at the Thai-Cambodian border. It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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