ORCID Profile
0000-0002-4802-0647
Current Organisation
Burnet Institute
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Publisher: Springer Science and Business Media LLC
Date: 02-12-2020
DOI: 10.1038/S41467-020-19988-Z
Abstract: Malaria is spread by the transmission of sexual stage parasites, called gametocytes. However, with Plasmodium falciparum , gametocytes can only be detected in peripheral blood when they are mature and transmissible to a mosquito, which complicates control efforts. Here, we identify the set of genes overexpressed in patient blood s les with high levels of gametocyte-committed ring stage parasites. Expression of all 18 genes is regulated by transcription factor AP2-G, which is required for gametocytogenesis. We select three genes, not expressed in mature gametocytes, to develop as biomarkers. All three biomarkers we validate in vitro using 6 different parasite lines and develop an algorithm that predicts gametocyte production in ex vivo s les and volunteer infection studies. The biomarkers are also sensitive enough to monitor gametocyte production in asymptomatic P. falciparum carriers allowing early detection and treatment of infectious reservoirs, as well as the in vivo analysis of factors that modulate sexual conversion.
Publisher: Public Library of Science (PLoS)
Date: 21-08-2020
Publisher: Public Library of Science (PLoS)
Date: 07-05-2020
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2019
DOI: 10.1101/776781
Abstract: Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax . Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from −1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.
Publisher: Public Library of Science (PLoS)
Date: 07-07-2015
Publisher: FapUNIFESP (SciELO)
Date: 08-2011
DOI: 10.1590/S0074-02762011000900016
Abstract: Drug resistance is one of the principal obstacles blocking worldwide malaria control. In Colombia, malaria remains a major public health concern and drug-resistant parasites have been reported. In vitro drug susceptibility assays are a useful tool for monitoring the emergence and spread of drug-resistant Plasmodium falciparum. The present study was conducted as a proof of concept for an antimalarial drug resistance surveillance network based on in vitro susceptibility testing in Colombia. Sentinel laboratories were set up in three malaria endemic areas. The enzyme linked immunosorbent assay-histidine rich protein 2 and schizont maturation methods were used to assess the susceptibility of fresh P. falciparum isolates to six antimalarial drugs. This study demonstrates that an antimalarial drug resistance surveillance network based on in vitro methods is feasible in the field with the participation of a research institute, local health institutions and universities. It could also serve as a model for a regional surveillance network. Preliminary susceptibility results showed widespread chloroquine resistance, which was consistent with previous reports for the Pacific region. However, high susceptibility to dihydroartemisinin and lumefantrine compounds, currently used for treatment in the country, was also reported. The implementation process identified critical points and opportunities for the improvement of network sustainability strategies.
Publisher: American Society for Microbiology
Date: 2016
DOI: 10.1128/AAC.02207-15
Abstract: Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o ( pvcrt-o ) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5 P 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2016
Publisher: Public Library of Science (PLoS)
Date: 27-10-2016
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-10-2010
Publisher: Springer Science and Business Media LLC
Date: 27-08-2019
Publisher: Oxford University Press (OUP)
Date: 29-10-2020
Abstract: Artemisinin derivatives are the leading class of antimalarial drugs due to their rapid onset of action and rapid clearance of circulating parasites. The parasite clearance half-life measures the rate of loss of parasites from blood after treatment, and this is currently used to assess antimalarial activity of novel agents and to monitor resistance. However, a number of recent studies have challenged the use of parasite clearance to measure drug activity, arguing that many circulating parasites may be nonviable. Plasmodium falciparum–infected subjects (n = 10) in a malaria volunteer infection study were administered a single dose of artesunate (2 mg/kg). Circulating parasite concentration was assessed by means of quantitative polymerase chain reaction (qPCR). Parasite viability after artesunate administration was estimated by mathematical modeling of the ex vivo growth of parasites collected from subjects. We showed that in artemisinin-sensitive infection, viable parasites declined to & .1% of baseline within 8 hours after artesunate administration, while the total number of circulating parasites measured with quantitative polymerase chain reaction remained unchanged. In artemisinin-resistant infections over the same interval, viable parasites declined to 51.4% (standard error of the mean, 4.6%) of baseline. These results demonstrate that in vivo drug activity of artesunate is faster than is indicated by the parasite clearance half-life.
Publisher: Cold Spring Harbor Laboratory
Date: 27-10-2020
DOI: 10.1101/2020.10.26.20214619
Abstract: Containing the spread of artemisinin (ART)-resistant Plasmodium falciparum will be assisted by improved understanding of its human-to-mosquito transmission. We compared gametocyte dynamics among field isolates containing K13 mutations conferring ART resistance and K13 wild-type parasites. In Pailin, Cambodia, the male to female gametocyte ratio was higher among K13 mutant infections compared to K13 wild-type infections. We also investigated the effects of artesunate and atovaquone-proguanil on the transmissibility of an ART-resistant K13 mutant strain, Cam3.II R539T , in a volunteer infection study. Gametocyte production was higher after a single dose of artesunate (2 mg/kg) in volunteers infected with ART-resistant compared to ART-sensitive parasites. Despite the presence of gametocytes in volunteers infected with ART-resistant parasites, there was no infection observed in Anopheles stephensi mosquitoes after atovaquone-proguanil treatment. We report transmission determinants of ART-resistant infections that could be advantageous over ART-sensitive infections. Moreover, we show additional benefits of treating ART-resistant infections with atovaquone-proguanil treatment.
No related grants have been discovered for Zuleima Pava.