ORCID Profile
0000-0002-1189-2310
Current Organisations
Monash University
,
Deakin University
,
The Walter and Eliza Hall Institute
,
University of Melbourne
,
Burnet Institute
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Publisher: Oxford University Press (OUP)
Date: 02-1999
DOI: 10.1093/HMG/8.2.217
Abstract: We previously described the cloning of an 80 kb DNA corresponding to the core protein-binding domain of a human chromosome 10-derived neocentromere. Here we report the complete sequence of this DNA (designated NC DNA) and its detailed structural analysis. The sequence is devoid of human centromeric alpha-satellite DNA and the pericentric beta- and gamma-satellites, the ATRS and 48 bp repeat DNA. One copy of a sequence that is related to the CENPB box motif is present, and a number of copies of other pericentric sequences including pJalpha and classical satellites I and III are present but both their relative sparsity and non-tandem organization suggest that each sequence, on its own, is unlikely to mimic any role the sequence may have in the normal centromere. The DNA-binding motifs of the architectural and regulatory proteins HMGI and topoII have a normal abundance and random distribution, implying that these sequences are not key functional elements. The total A + T content of the sequence is not notably different from that of the human genome, but an abundance of AT-rich islands and a biased distribution of these islands within the NC sequence are clearlydiscernible and may be functionally significant. Substantial amounts of transposable elements and low copy number tandem repeats, including several that are highly AT- and purine-rich, are also present and may act as functional elements. One of the AT-rich tandemrepeats (AT28) may form interesting structures and is described in detail. The defined features show only a loose resemblance to the structures of known centromeres, highlighting the possibility that, rather than a conserved primary sequence, it is the overallcomposition and distribution patterns of various unknown functional elements, or any 'ordinary' DNA under appropriate epigenetic influences, that determine centromere formation and function. This is the firstdetailed analysis of a neocentromere DNA and provides a basis for comparison against future sequences.
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2022
DOI: 10.1101/2022.09.29.510018
Abstract: With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum . We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell invasion, and have generated analogues with improved potency. Here, we identify actin and profilin as putative targets of the MMV020291 series through resistance selection and whole genome sequencing of three MMV020291 resistant populations. This revealed three non-synonymous single nucleotide polymorphisms in two genes two in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wildtype parasites which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade red blood cells. Additionally, the series inhibits the actin-1 dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro co-sedimentation experiments using recombinant P. falciparum actin-1 and profilin proteins indicate that potent MMV020291 analogues lify the actin-monomer sequestering effect of profilin, thereby reducing the formation of filamentous actin. Altogether, this study identifies the first compound series targeting the actin-1 rofilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.
Publisher: Public Library of Science (PLoS)
Date: 2007
Publisher: Elsevier BV
Date: 08-2003
Publisher: Springer Science and Business Media LLC
Date: 20-10-2020
DOI: 10.1186/S12936-020-03440-0
Abstract: Genomic surveillance of malaria parasite populations has the potential to inform control strategies and to monitor the impact of interventions. Barcodes comprising large numbers of single nucleotide polymorphism (SNP) markers are accurate and efficient genotyping tools, however may need to be tailored to specific malaria transmission settings, since ‘universal’ barcodes can lack resolution at the local scale. A SNP barcode was developed that captures the ersity and structure of Plasmodium vivax populations of Papua New Guinea (PNG) for research and surveillance. Using 20 high-quality P. vivax genome sequences from PNG, a total of 178 evenly spaced neutral SNPs were selected for development of an licon sequencing assay combining a series of multiplex PCRs and sequencing on the Illumina MiSeq platform. For initial testing, 20 SNPs were lified in a small number of mono- and polyclonal P. vivax infections. The full barcode was then validated by genotyping and population genetic analyses of 94 P. vivax isolates collected between 2012 and 2014 from four distinct catchment areas on the highly endemic north coast of PNG. Diversity and population structure determined from the SNP barcode data was then benchmarked against that of ten microsatellite markers used in previous population genetics studies. From a total of 28,934,460 reads generated from the MiSeq Illumina run, 87% mapped to the PvSalI reference genome with deep coverage (median = 563, range 56–7586) per locus across genotyped s les. Of 178 SNPs assayed, 146 produced high-quality genotypes (minimum coverage = 56X) in more than 85% of P. vivax isolates. No lification bias was introduced due to either polyclonal infection or whole genome lification (WGA) of s les before genotyping. Compared to the microsatellite panels, the SNP barcode revealed greater variability in genetic ersity between populations and geographical population structure. The SNP barcode also enabled assignment of genotypes according to their geographic origins with a significant association between genetic distance and geographic distance at the sub-provincial level. High-throughput SNP barcoding can be used to map variation of malaria transmission dynamics at sub-national resolution. The low cost per s le and genotyping strategy makes the transfer of this technology to field settings highly feasible.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S1471-4922(02)02268-7
Abstract: Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the ersification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today's population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today's population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies.
Publisher: Public Library of Science (PLoS)
Date: 06-10-2016
Publisher: American Society of Tropical Medicine and Hygiene
Date: 09-01-2017
Publisher: Oxford University Press (OUP)
Date: 19-09-2017
Publisher: Public Library of Science (PLoS)
Date: 21-05-2015
Publisher: Springer Science and Business Media LLC
Date: 28-03-2019
Publisher: Cold Spring Harbor Laboratory
Date: 26-04-2023
DOI: 10.1101/2023.04.25.538349
Abstract: With resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250, was prioritised for further optimisation. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite’s life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB which clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies which showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.
Publisher: Cold Spring Harbor Laboratory
Date: 04-09-2023
Publisher: American Society for Microbiology
Date: 08-2018
DOI: 10.1128/IAI.00485-17
Abstract: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3 PF11_0521 , in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 31-10-2016
Publisher: Public Library of Science (PLoS)
Date: 20-09-2012
Publisher: Public Library of Science (PLoS)
Date: 02-02-2022
DOI: 10.1371/JOURNAL.PCBI.1009801
Abstract: Investigation of the ersity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum , have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global ersity and population structure of leading vaccine candidate antigens of P . falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene ‘haplotypes’ from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp , trap , eba175 , ama1 , rh5 , and CelTOS . Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of ersity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the ersity of P . falciparum antigens to be considered in the design of the next generation of malaria vaccines.
Publisher: Public Library of Science (PLoS)
Date: 16-03-2007
Publisher: Elsevier BV
Date: 06-2020
Publisher: Cambridge University Press (CUP)
Date: 08-01-2016
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.IJPARA.2016.08.006
Abstract: Molecular approaches have an increasingly recognized utility in surveillance of malaria parasite populations, not only in defining prevalence and incidence with higher sensitivity than traditional methods, but also in monitoring local and regional parasite transmission patterns. In this review, we provide an overview of population genetic and genomic studies of human-infecting Plasmodium species, highlighting recent advances in the field. In accordance with the renewed impetus for malaria eradication, many studies are now using genetic and genomic epidemiology to support local evidence-based intervention strategies. Microsatellite genotyping remains a popular approach for both Plasmodium falciparum and Plasmodium vivax. However, with the increasing availability of whole genome sequencing data enabling effective single nucleotide polymorphism-based panels tailored to a given study question and setting, this approach is gaining popularity. The availability of new reference genomes for Plasmodium malariae and Plasmodium ovale should see a surge in similar molecular studies on these currently neglected species. Genomic studies are revealing new insights into important adaptive mechanisms of the parasite including antimalarial drug resistance. The advent of new methodologies such as selective whole genome lification for dealing with extensive human DNA in low density field isolates should see genome-wide approaches becoming routine for parasite surveillance once the economic costs outweigh the current cost benefits of targeted approaches.
Publisher: Elsevier BV
Date: 11-2011
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-07-2013
Publisher: The American Association of Immunologists
Date: 15-11-2010
Abstract: Abs targeting blood-stage Ags of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologs (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight recombinant proteins covering the entire PfRh2 common region, as well as PfRh2a- and PfRh2b-specific regions. Abs were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 mo for reinfection and malaria. At baseline, Abs were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high-density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analyzed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein and seem to be under ersifying selection, suggesting immune pressure. Cluster analysis arranged the sequences into two main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans and that Abs act by controlling blood-stage parasitemia and support its potential for vaccine development.
Publisher: Wiley
Date: 16-10-2020
DOI: 10.1111/MEC.15654
Publisher: Public Library of Science (PLoS)
Date: 03-08-2020
Publisher: Elsevier BV
Date: 2007
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-07-2001
Abstract: Genetic variability of Plasmodium falciparum underlies its transmission success and thwarts efforts to control disease caused by this parasite. Genetic variation in antigenic, drug resistance, and pathogenesis determinants is abundant, consistent with an ancient origin of P. falciparum , whereas DNA variation at silent (synonymous) sites in coding sequences appears virtually absent, consistent with a recent origin of the parasite. To resolve this paradox, we analyzed introns and demonstrated that these are deficient in single-nucleotide polymorphisms, as are synonymous sites in coding regions. These data establish the recent origin of P. falciparum and further provide an explanation for the abundant ersity observed in antigen and other selected genes.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 03-04-2013
Publisher: Wiley
Date: 2015
DOI: 10.1111/MEC.13033
Abstract: Plasmodium falciparum malaria is a major global health problem that is being targeted for progressive elimination. Knowledge of local disease transmission patterns in endemic countries is critical to these elimination efforts. To investigate fine-scale patterns of malaria transmission, we have compared repertoires of rapidly evolving var genes in a highly endemic area. A total of 3680 high-quality DBLα-sequences were obtained from 68 P. falciparum isolates from ten villages spread over two distinct catchment areas on the north coast of Papua New Guinea (PNG). Modelling of the extent of var gene ersity in the two parasite populations predicts more than twice as many var gene alleles circulating within each catchment (Mugil = 906 Wosera = 1094) than previously recognized in PNG (Amele = 369). In addition, there were limited levels of var gene sharing between populations, consistent with local parasite population structure. Phylogeographic analyses demonstrate that while neutrally evolving microsatellite markers identified population structure only at the catchment level, var gene repertoires reveal further fine-scale geospatial clustering of parasite isolates. The clustering of parasite isolates by village in Mugil, but not in Wosera was consistent with the physical and cultural isolation of the human populations in the two catchments. The study highlights the microheterogeneity of P. falciparum transmission in highly endemic areas and demonstrates the potential of var genes as markers of local patterns of parasite population structure.
Publisher: Research Square Platform LLC
Date: 22-01-2020
Abstract: Background In the past decade, national malaria control efforts in Papua New Guinea (PNG) have received renewed support, facilitating nationwide distribution of free long-lasting insecticidal nets (LLINs), as well as improvements in access to parasite-confirmed diagnosis and effective artemisinin-combination therapy in 2011-12. Methods To study the effects of these intensified control efforts on the epidemiology and transmission of P. falciparum and P. vivax infections and investigate risk factors at the in idual and household level, two cross-sectional surveys were conducted in the East Sepik Province of PNG one in 2005, before the scale-up of national c aigns and one in late 2012-early 2013, after 2 rounds of LLIN distribution (2008 and 2011-12). Differences between studies were investigated using chi-square (χ²), Fischer’s exact tests and Student’s t-test. Multivariable logistic regression models were built to investigate factors associated with infection at the in idual and household level. Results The prevalence of P. falciparum and P. vivax in surveyed communities decreased from 55% (2005) to 9% (2013) and 36% to 6%, respectively. The mean multiplicity of infection (MOI) decreased from 1.8 to 1.6 for P. falciparum (p=0.08) and from 2.2 to 1.4 for P. vivax (p .001). Alongside these reductions, a shift towards a more uniform distribution of infections and illness across age groups was observed but there was greater heterogeneity across the study area and within the study villages. Microscopy positive infections and clinical cases in the household were associated with high rate infection households ( % of household members with Plasmodium infection). Conclusion After the scale-up of malaria control interventions in PNG between 2008 and 2012, there was a substantial reduction in P. falciparum and P. vivax infection rates in the studies villages in East Sepik Province. Understanding the extent of local heterogeneity in malaria transmission and the driving factors is critical to identify and implement targeted control strategies to ensure the ongoing success of malaria control in PNG and inform the development of tools required to achieve elimination. In household-based interventions, diagnostics with a sensitivity similar to (expert) microscopy could be used to identify and target high rate households.
Publisher: Cold Spring Harbor Laboratory
Date: 06-2000
DOI: 10.1101/GR.10.6.832
Abstract: We have previously localized the core centromere protein-binding domain of a 10q25.2-derived neocentromere to an 80-kb genomic region. Detailed analysis has indicated that the 80-kb neocentromere (NC) DNA has a similar overall organization to the corresponding region on a normal chromosome 10 (HC) DNA, derived from a genetically unrelated CEPH in idual. Here we report sequencing of the HC DNA and its comparison to the NC sequence. Single-base differences were observed at a maximum rate of 4.6 per kb however, no deletions, insertions, or other structural rearrangements were detected. To investigate whether the observed changes, or subsets of these, might be de novo mutations involved in neocentromerization (i.e., in committing a region of a chromosome to neocentromere formation), the progenitor DNA (PnC) from which the NC DNA descended, was cloned and sequenced. Direct comparison of the PnC and NC sequences revealed 100% identity, suggesting that the differences between NC and HC DNA are single nucleotide polymorphisms (SNPs) and that formation of the 10q25.2 NC did not involve a change in DNA sequence in the core centromere protein-binding NC region. This is the first study in which a cloned NC DNA has been compared directly with its inactive progenitor DNA at the primary sequence level. The results form the basis for future sequence comparison outside the core protein-binding domain, and provide direct support for the involvement of an epigenetic mechanism in neocentromerization. [The sequences in this paper have been submitted to GenBank under accession nos. AF222855 (not yet available) for HC AF042484 for NCI AF222854 (not yet available) for NCII and AF222856 (not yet available) for PnC.]
Publisher: Frontiers Media SA
Date: 28-07-2014
Publisher: Elsevier BV
Date: 12-2013
Abstract: Malaria is a major cause of morbidity and mortality. Immunity is acquired but is suboptimal, being slow to develop and incomplete. An inadequate understanding of natural immunity, host-parasite interactions, and a lack of reliable immune correlates of protection that could predict vaccine efficacy in the field have hindered development of a vaccine. With data from Phase III trials indicating that the leading malaria vaccine candidate, RTS,S, has limited efficacy, it is necessary to reconsider approaches to the development of a vaccine capable of inducing long-lived protection.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
DOI: 10.1186/S12936-020-03330-5
Abstract: The Asia–Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia–Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process.
Publisher: Cold Spring Harbor Laboratory
Date: 19-11-2021
DOI: 10.1101/2021.11.16.468904
Abstract: Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an in idual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of ersity and selection, and 3-dimensional (3D) visualisation of genotypic information encoded in Variant Call Format (VCF) on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritising targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum , revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.
Publisher: Informa UK Limited
Date: 18-04-2015
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2022
DOI: 10.1101/2022.02.24.481744
Abstract: The complex life cycle of Plasmodium parasites, the eukaryotic pathogens that cause malaria, features three distinct invasive forms tailored specifically to the equally distinct host environment they must navigate and invade for progression of the life cycle. One conserved feature of all these invasive forms is the presence of micronemes, apically oriented secretory organelles involved in egress, motility, adhesion and invasion. Micronemes are tailored to their specific host environment and feature stage specific contents. Here we investigate the role of GPI-anchored micronemal antigen (GAMA), which shows a micronemal localization in all zoite forms of the rodent infecting species Plasmodium berghei . While GAMA is dispensable during asexual blood stages, GAMA knock out parasites are severely defective for invasion of the mosquito midgut, resulting in reduced numbers of oocysts. Once formed, oocysts develop normally, however sporozoites are unable to egress and these sporozoites exhibit defective motility. Epitope-tagging of GAMA revealed tight temporal expression late during sporogony and showed that GAMA is shed during sporozoite gliding motility in a similar manner to circumsporozoite protein. Complementation of P. berghei knock out parasites with full length P. falciparum GAMA partially restored infectivity to mosquitoes, indicating a conservation of function across Plasmodium species. A suite of parasites with GAMA expressed under the promoters of the known ookinete-to-sporozoite stage-specific genes: CTRP, CAP380 and TRAP, further confirmed the involvement of GAMA in midgut infection, motility and infection of the mammalian host and revealed a lethal consequence to overexpression of GAMA during oocyst development. Combined, the research suggest that GAMA plays independent roles in sporozoite motility, egress and invasion, possibly implicating GAMA as a regulator of microneme function. Malaria remains a major source of morbidity and mortality across the globe. Completion of a complex life cycle between vertebrates and mosquitoes is required for the maintenance of parasite populations and the persistence of malaria disease and death. Three invasive forms across the complex lifecycle of the parasite must successfully egress and invade specific cell types within the vertebrate and mosquito hosts to maintain parasite populations and consequently disease and suffering. A conserved feature of all invasive forms are the micronemes, apically oriented secretory organelles which contain proteins required for motility, egress and invasion. Few proteins are expressed in the micronemes of all three invasive forms. One such protein is GPI-anchored micronemal antigen (GAMA). Here we reveal that GAMA is required for the invasion of the mosquito midgut, egress of sporozoites from oocysts and invasion of the vertebrate host. Our finding indicate that while GAMA is essential for sporozoite motility, the defects in oocyst egress and hepatocyte invasion occur independently of the motility defect, implicating the requirement of GAMA in all three processes.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2014
Publisher: Elsevier BV
Date: 04-2018
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: American Society of Tropical Medicine and Hygiene
Date: 02-09-2015
Publisher: Public Library of Science (PLoS)
Date: 27-12-2017
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1186/S12916-021-01993-8
Abstract: In the Greater Mekong Subregion (GMS), current malaria surveillance strategies rely on a network of village health volunteers (VHVs) reporting the results of rapid diagnostic tests (RDTs), known to miss many asymptomatic infections. Integration of more sensitive diagnostic molecular and serological measures into the VHV network may improve surveillance of residual malaria transmission in hard-to-reach areas in the region and inform targeted interventions and elimination responses. However, data on residual malaria transmission that would be captured by these measures in the VHV-led testing and treatment surveillance network in the GMS is unknown. A total of 114 VHVs were trained to collect dried blood spots from villagers undergoing routine RDTs as part of VHV-led active and passive case detection from April 2015 to June 2016. S les were subjected to molecular testing (quantitative polymerase chain reaction [qPCR]) to determine Plasmodium falciparum and P. vivax infection and serological testing (against P. falciparum and P. vivax antigens) to determine exposure to P. falciparum and P. vivax . Over 15 months, 114 VHVs performed 32,194 RDTs and collected s les for molecular ( n = 13,157) and serological ( n = 14,128) testing. The prevalence of molecular-detectable P. falciparum and P. vivax infection was 3.2% compared to the 0.16% prevalence of Plasmodium spp. by RDT, highlighting the large burden of infections undetected by standard surveillance. Peaks in anti- P. falciparum , but not P. vivax , merozoite IgG seroprevalence coincided with seasonal P. falciparum transmission peaks, even in those with no molecularly detectable parasites. At the in idual level, antibody seropositivity was associated with reduced odds of contemporaneous P. falciparum (OR for Pf CSP 0.51 [95%CI 0.35, 0.76], p = 0.001, Pf AMA1 0.70 [95%CI 0.52, 0.93], p = 0.01, and Pf MSP2 0.81 [95%CI 0.61, 1.08], p = 0.15), but not P. vivax infection (OR Pv AMA1 1.02 [95%CI 0.73, 1.43], p = 0.89) indicating a potential role of immunity in protection against molecular-detectable P. falciparum parasitaemia. We demonstrated that integration and implementation of s le collection for molecular and serological surveillance into networks of VHV servicing hard-to-reach populations in the GMS is feasible, can capture significant levels of ongoing undetected seasonal malaria transmission and has the potential to supplement current routine RDT testing. Improving malaria surveillance by advancing the integration of molecular and serological techniques, through centralised testing approaches or novel point-of-contact tests, will advance progress, and tracking, towards malaria elimination goals in the GMS.
Publisher: Public Library of Science (PLoS)
Date: 23-05-2018
Publisher: Cold Spring Harbor Laboratory
Date: 26-06-2021
DOI: 10.1101/2021.06.21.21259065
Abstract: Investigation of the ersity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies on Plasmodium falciparum antigen ersity have focused on well-known vaccine candidates while the ersity of several others has never been studied. Here we provide an overview of the ersity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. We developed a stringent variant calling pipeline to extract high quality antigen gene sequences from the global dataset and a new R-package named VaxPack to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp , trap , eba175 , ama1 , rh5 , and CelTOS . We found that current malaria vaccine formulations are based on rare variants and thus may have limited efficacy. High levels of ersity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptations to different human host or mosquito vector populations. This study provides an essential framework for the ersity of P. falciparum antigens for inclusion in the design of the next generation of malaria vaccines. Highly effective malaria vaccines are important for the sustainable elimination of malaria. However, the ersity of parasite antigens targeted by malaria vaccines has been largely overlooked, with most vaccine formulations based only on a single antigen variant. Failure to accommodate this ersity may result in vaccines only being effective against vaccine-like variants, resulting in limited protective efficacy. Investigation of the ersity of genes encoding parasite antigens can help prioritize and validate them as vaccine candidates as well as to identify the most common variants for inclusion in the next generation of malaria vaccines. Here we measure the ersity of 23 vaccine antigens of Plasmodium falciparum , using the publicly available MalariaGEN Pf3K (version 5.1) resource comprising more than 2600 genomes from 15 malaria endemic countries. We found that variants found in current vaccine formulations are rare and thus may target only a small proportion of circulating malaria parasite strains. Variation in intensity of immune selection in parasites from different geographic areas suggests adaptation to different human host or vector populations. This study provides an essential framework for the design of the next generation of malaria vaccines, in addition to providing novel insights into malaria biology.
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2020
DOI: 10.1101/2020.12.17.423341
Abstract: Malaria parasite genomes have been generated predominantly using short read sequencing technology which can be slow, requires advanced laboratory training and does not adequately interrogate complex genomic regions that harbour important malaria virulence determinants. The portable Oxford Nanopore Technologies MinION platform generates long reads in real time and may overcome these limitations. We present compelling evidence that Nanopore sequencing delivers valuable additional information for malaria parasites with comparable data fidelity for single nucleotide variant (SNV) calls, compared to standard Illumina whole genome sequencing. We demonstrate this through sequencing of pure Plasmodium falciparum DNA, mock infections and natural isolates. Nanopore has low error rates for haploid SNV genotyping and identifies structural variants (SVs) not detected with short reads. Nanopore genomes are directly comparable to publically available genomes and produce high quality end to end chromosome assemblies. Nanopore sequencing will expedite genomic surveillance of malaria and provide new insights into parasite genome biology.
Publisher: Public Library of Science (PLoS)
Date: 25-05-2021
DOI: 10.1371/JOURNAL.PGEN.1009576
Abstract: In iduals acquire immunity to clinical malaria after repeated Plasmodium falciparum infections. Immunity to disease is thought to reflect the acquisition of a repertoire of responses to multiple alleles in erse parasite antigens. In previous studies, we identified polymorphic sites within in idual antigens that are associated with parasite immune evasion by examining antigen allele dynamics in in iduals followed longitudinally. Here we expand this approach by analyzing genome-wide polymorphisms using whole genome sequence data from 140 parasite isolates representing malaria cases from a longitudinal study in Malawi and identify 25 genes that encode possible targets of naturally acquired immunity that should be validated immunologically and further characterized for their potential as vaccine candidates.
Publisher: Springer Science and Business Media LLC
Date: 06-1997
DOI: 10.1038/NG0697-144
Abstract: We recently described a human marker chromosome containing a functional neo-centromere that binds anti-centromere antibodies, but is devoid of centromeric alpha-satellite repeats and derived from a hitherto non-centromeric region of chromosome 10q25. Chromosome walking using cloned single-copy DNA from this region enabled us to identify the antibody-binding domain of this centromere. Extensive restriction mapping indicates that this domain has an identical genomic organization to the corresponding normal chromosomal region, suggesting a mechanism for the origin of this centromere through the activation of a latent centromere that exists within 10q25.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2010
Abstract: The South West Pacific nation of Papua New Guinea has intense year round transmission of Plasmodium falciparum on the coast and in the low-lying inland areas. Local heterogeneity in the epidemiology of malaria suggests that parasites from multiple locations will need to be surveyed to define the population biology of P. falciparum in the region. This study describes the population genetics of P. falciparum in thirteen villages spread over four distinct catchment areas of Papua New Guinea. Ten microsatellite loci were genotyped in 318 P. falciparum isolates from the parasite populations of two inland catchment areas, namely Wosera (number of villages (n) = 7) and Utu (n = 1) and and two coastal catchments, Malala (n = 3) and Mugil (n = 3). Analysis of the resultant multilocus haplotypes was done at different spatial scales (2-336 km) to define the genetic ersity (allelic richness and expected heterozygosity), linkage disequilibrium and population structure throughout the study area. Although genetic ersity was high in all parasite populations, it was also variable with a lower allelic richness and expected heterozygosity for inland populations compared to those from the more accessible coast. This variability was not correlated with two proxy measures of transmission intensity, the infection prevalence and the proportion multiple infections. Random associations among the microsatellite loci were observed in all four catchments showing that a substantial degree of out-crossing occurs in the region. Moderate to very high levels of population structure were found but the amount of genetic differentiation ( F ST ) did not correlate with geographic distance suggesting that parasite populations are fragmented. Population structure was also identified between villages within the Malala area, with the haplotypes of one parasite population clustering with the neighbouring catchment of Mugil. The observed population genetics of P. falciparum in this region is likely to be a consequence of the high transmission intensity combined with the isolation of human and vector populations, especially those located inland and migration of parasites via human movement into coastal populations. The variable genetic ersity and population structure of P. falciparum has important implications for malaria control strategies and warrants further fine scale s ling throughout Papua New Guinea.
Publisher: Cold Spring Harbor Laboratory
Date: 19-11-2018
DOI: 10.1101/472159
Abstract: Extreme ersity of the major surface antigen and virulence determinant of the malaria parasite Plasmodium falciparum , Erythrocyte Membrane Protein-1 (PfEMP1), poses a major barrier to identifying targets of protective immunity. To overcome this problem, we developed a PfEMP1 protein microarray containing 456 DBLα domains, which was used to characterize the immunome of a cohort of semi-immune children and to identify variants associated with protective immune responses. Children with high mean antibody levels to DBLα group 2 had a 26-36% reduced risk of uncomplicated (clinical) malaria, however only 8 erse DBLα variants were weakly associated with protection from clinical malaria and had low predictive accuracy. On the other hand, children with high mean antibodies to DBLα groups 1 and 2 (which are markers for pathogenic “Type A” PfEMP1) and elevated antibodies to 85 (18.6%) of in idual DBLα variants had a 70 −100% reduced risk of severe malaria. Of the top 20 predictive variants for severe disease protection, 17 were strongly associated with protection (86 - 100% reduction in risk of severe malaria) and had high predictive accuracy for severe disease risk. Many variants were conserved and had highly correlated antibody responses, including the three highest-ranking variants, which were linked to EPCR-binding CIDR domains. The results suggest that while immunity to uncomplicated malaria is characterised by antibodies to a erse repertoire of PfEMP1, immunity to severe malaria requires antibodies to a limited subset of antigenically conserved variants. These findings provide new insights into antimalarial immunity and potential biomarkers for tracking disease risk.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2012
Abstract: Traditionally, infection with Plasmodium vivax was thought to be benign and self-limiting, however, recent evidence has demonstrated that infection with P. vivax can also result in severe illness and death. Research into P. vivax has been relatively neglected and much remains unknown regarding the biology, pathogenesis and epidemiology of this parasite. One of the fundamental factors governing transmission and immunity is parasite ersity. An understanding of parasite population genetic structure is necessary to understand the epidemiology, ersity, distribution and dynamics of natural P. vivax populations. In addition, studying the population structure of genes under immune selection also enables investigation of the dynamic interplay between transmission and immunity, which is crucial for vaccine development. A lack of knowledge regarding the transmission and spread of P. vivax has been particularly highlighted in areas where malaria control and elimination programmes have made progress in reducing the burden of Plasmodium falciparum , yet P. vivax remains as a substantial obstacle. With malaria elimination back on the global agenda, mapping of global and local P. vivax population structure is essential prior to establishing goals for elimination and the roll-out of interventions. A detailed knowledge of the spatial distribution, transmission and clinical burden of P. vivax is required to act as a benchmark against which control targets can be set and measured. This paper presents an overview of what is known and what is yet to be fully understood regarding P. vivax population genetics, as well as the importance and application of P. vivax population genetics studies.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3599
Publisher: Public Library of Science (PLoS)
Date: 26-10-2012
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 05-06-2020
DOI: 10.1186/S12936-020-03265-X
Abstract: In the past decade, national malaria control efforts in Papua New Guinea (PNG) have received renewed support, facilitating nationwide distribution of free long-lasting insecticidal nets (LLINs), as well as improvements in access to parasite-confirmed diagnosis and effective artemisinin-combination therapy in 2011–2012. To study the effects of these intensified control efforts on the epidemiology and transmission of Plasmodium falciparum and Plasmodium vivax infections and investigate risk factors at the in idual and household level, two cross-sectional surveys were conducted in the East Sepik Province of PNG one in 2005, before the scale-up of national c aigns and one in late 2012-early 2013, after 2 rounds of LLIN distribution (2008 and 2011–2012). Differences between studies were investigated using Chi square (χ 2 ), Fischer’s exact tests and Student’s t-test. Multivariable logistic regression models were built to investigate factors associated with infection at the in idual and household level. The prevalence of P. falciparum and P. vivax in surveyed communities decreased from 55% (2005) to 9% (2013) and 36% to 6%, respectively. The mean multiplicity of infection (MOI) decreased from 1.8 to 1.6 for P. falciparum (p = 0.08) and from 2.2 to 1.4 for P. vivax (p 0.001). Alongside these reductions, a shift towards a more uniform distribution of infections and illness across age groups was observed but there was greater heterogeneity across the study area and within the study villages. Microscopy positive infections and clinical cases in the household were associated with high rate infection households ( 50% of household members with Plasmodium infection). After the scale-up of malaria control interventions in PNG between 2008 and 2012, there was a substantial reduction in P. falciparum and P. vivax infection rates in the studies villages in East Sepik Province. Understanding the extent of local heterogeneity in malaria transmission and the driving factors is critical to identify and implement targeted control strategies to ensure the ongoing success of malaria control in PNG and inform the development of tools required to achieve elimination. In household-based interventions, diagnostics with a sensitivity similar to (expert) microscopy could be used to identify and target high rate households.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2022
DOI: 10.1186/S12961-022-00840-3
Abstract: Successful implementation research requires effective and equitable relationships between policy-makers, researchers and implementers to effect evidence-based systems change. However, mainstream research grant models between Global North and Global South institutions often (unintentionally) reinforce power imbalances between partners, which result in missed opportunities for knowledge and learning exchange between policy-makers, researchers and implementers. This case study, centred on the STRIVE PNG project, describes how a partnership-based approach has been used to establish, maintain and review effective and equitable relationships between 13 partner organizations (independent research institutes, government health agencies and public health laboratories) to strengthen surveillance and health systems in Papua New Guinea (PNG). We provide an overview of key terms (with supporting conceptual frameworks), describe selected partnership processes and tools used within the project, and share observations regarding early outcomes achieved through this approach.
Publisher: Public Library of Science (PLoS)
Date: 20-08-2020
Publisher: Public Library of Science (PLoS)
Date: 15-12-2020
DOI: 10.1371/JOURNAL.PPAT.1009133
Abstract: The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical s les. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical s les from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1 , ferredoxin , atg18 and pnp . These findings suggest that a P . falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2021
DOI: 10.1101/2021.05.19.444768
Abstract: Short tandem repeats (STRs) are highly informative genetic markers that have been used extensively in population genetics analysis. They are an important source of genetic ersity and can also have functional impact. Despite the availability of bioinformatic methods that permit large-scale genome-wide genotyping of STRs from whole genome sequencing data, they have not previously been applied to sequencing data from large collections of malaria parasite field s les. Here, we have genotyped STRs using HipSTR in more than 3,000 Plasmodium falciparum and 174 Plasmodium vivax published whole-genome sequence data from s les collected across the globe. High levels of noise and variability in the resultant callset necessitated the development of a novel method for quality control of STR genotype calls. A set of high-quality STR loci (6,768 from P. falciparum and 3,496 from P. vivax ) were used to study Plasmodium genetic ersity, population structures and genomic signatures of selection and these were compared to genome-wide single nucleotide polymorphism (SNP) genotyping data. In addition, the genome-wide information about genetic variation and other characteristics of STRs in P. falciparum and P. vivax have been made available in an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ). Malaria is a severe disease caused by a genus of parasites called Plasmodium and is transmitted to humans through infected Anopheles mosquitoes. P. falciparum and P. vivax are the predominant species responsible for more than 95% of all human malaria infections which continue to pose a significant challenge to human health. Antimalarial drug resistance is a serious threat hindering the elimination of malaria. As such, it is important to understand the role of genomic variation in the development of antimalarial drug resistance. STRs are an important source of genomic variation that, from a population genetics perspective, have several advantages over SNPs, including being highly polymorphic, having a higher mutation rate, and having been widely used to study the population structure and genetic ersity. However, STRs are not routinely genotyped with bioinformatic tools across the whole genome with short read sequencing data because they are difficult to identify and genotype accurately, as they vary in size and may align poorly to the reference genome, therefore requiring rigorous quality control (QC). In this study, we genotype STRs using HipSTR[1] in more than 3,000 P. falciparum and 174 P. vivax whole-genome sequence s les collected world-wide. We develop a multivariable logistic regression model for the measurement and prediction of the quality of STRs. In addition, we use a set of genome-wide high-quality STRs to study parasite population genetics and compare them to genome-wide SNP genotyping data, revealing both high consistency with SNP based signals, as well as identifying some signals unique to the STR marker data. These results demonstrate that the identification of highly informative STR markers from large numbers of population s les is a powerful approach to study the genetic ersity, population structures and genomic signatures of selection in P. falciparum and P. vivax . Furthermore, we built an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ) that includes genome-wide information about genetic variation and other characteristics of the high quality STRs identified in P. falciparum and P. vivax , allowing researchers to explore and visualize the specific STRs.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2014
Publisher: Public Library of Science (PLoS)
Date: 15-04-2015
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.MEEGID.2017.11.028
Abstract: The Asia Pacific Leaders in Malaria Alliance (APLMA) have committed to eliminate malaria from the region by 2030. Papua New Guinea (PNG) has the highest malaria burden in the Asia-Pacific region but with the intensification of control efforts since 2005, transmission has been dramatically reduced and Plasmodium vivax is now the dominant malaria infection in some parts of the country. To gain a better understanding of the transmission dynamics and migration patterns of P. vivax in PNG, here we investigate population structure in eight geographically and ecologically distinct regions of the country. A total of 219 P. vivax isolates (16-30 per population) were successfully haplotyped using 10 microsatellite markers. A wide range of genetic ersity (H
Publisher: Public Library of Science (PLoS)
Date: 26-01-2018
Publisher: F1000 Research Ltd
Date: 13-07-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.2
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.GENE.2006.02.029
Abstract: An analysis of the ersity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5' flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite ersity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional ersity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the ersity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under ersifying selection, may contribute to the observed ersity. We discuss the importance of ersity and local selection effects when choosing drug targets for intervention strategies.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2011
Publisher: Public Library of Science (PLoS)
Date: 10-01-2022
DOI: 10.1371/JOURNAL.PGEN.1009604
Abstract: Short tandem repeats (STRs) are highly informative genetic markers that have been used extensively in population genetics analysis. They are an important source of genetic ersity and can also have functional impact. Despite the availability of bioinformatic methods that permit large-scale genome-wide genotyping of STRs from whole genome sequencing data, they have not previously been applied to sequencing data from large collections of malaria parasite field s les. Here, we have genotyped STRs using HipSTR in more than 3,000 Plasmodium falciparum and 174 Plasmodium vivax published whole-genome sequence data from s les collected across the globe. High levels of noise and variability in the resultant callset necessitated the development of a novel method for quality control of STR genotype calls. A set of high-quality STR loci (6,768 from P . falciparum and 3,496 from P . vivax ) were used to study Plasmodium genetic ersity, population structures and genomic signatures of selection and these were compared to genome-wide single nucleotide polymorphism (SNP) genotyping data. In addition, the genome-wide information about genetic variation and other characteristics of STRs in P . falciparum and P . vivax have been available in an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ).
Publisher: Elsevier BV
Date: 12-2021
Abstract: The human malaria parasite Plasmodium vivax commonly causes complex multiclonal infections. Recently, Dia et al. have developed innovative methods for single-cell sequencing (SCS) of P. vivax infections by adapting an approach used previously for Plasmodium falciparum. Their studies provide fascinating new insights into P. vivax intrahost ersity and evolution.
Publisher: Public Library of Science (PLoS)
Date: 30-12-2009
Publisher: Proceedings of the National Academy of Sciences
Date: 29-12-2016
Abstract: Plasmodium vivax is responsible for the most widely distributed recurring human malaria infections whereas Plasmodium falciparum inflicts the most mortality and morbidity in human populations. Malaria parasites enter our blood cells by making proteins that recognize and bind to their cognate receptors on the red blood cell surface. Our research describes, to our knowledge, the first crystal structure of PvRBP2a, an erythrocyte-binding protein from P. vivax, which revealed a structural scaffold similar to that of PfRh5, the essential erythrocyte-binding protein in P. falciparum . Structural comparisons between PvRBP2a and PfRh5 provide an important foundation toward understanding how P. vivax and P. falciparum parasites use a homologous erythrocyte-binding protein family to engage alternate erythrocyte receptors and ultimately govern host cell specificity.
Publisher: Public Library of Science (PLoS)
Date: 21-05-2015
Publisher: American Chemical Society (ACS)
Date: 11-03-2014
DOI: 10.1021/AC404188G
Abstract: Insecticide resistance is one of the most prevalent ex les of anthropogenic genetic change, yet our understanding of metabolic-based resistance remains limited by the analytical challenges associated with rapidly tracking the in vivo metabolites of insecticides at nonlethal doses. Here, using twin ion mass spectrometry analysis of the extracts of whole Drosophila larvae and excreta, we show that (i) eight metabolites of the neonicotinoid insecticide, imidacloprid, can be detected when formed by susceptible larval genotypes and (ii) the specific overtranscription of a single gene product, Cyp6g1, associated with the metabolic resistance to neonicotinoids, results in a significant increase in the formation of three imidacloprid metabolites that are formed in C-H bond activation reactions that is, Cyp6g1 is directly linked to the enhanced metabolism of imidacloprid in vivo. These results establish a rapid and sensitive method for dissecting the metabolic machinery of insects by directly linking single gene products to insecticide metabolism.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3588
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12916-019-1456-9
Abstract: As malaria transmission declines, understanding the differential impact of intensified control on Plasmodium falciparum relative to Plasmodium vivax and identifying key drivers of ongoing transmission is essential to guide future interventions. Three longitudinal child cohorts were conducted in Papua New Guinea before (2006/2007), during (2008) and after scale-up of control interventions (2013). In each cohort, children aged 1–5 years were actively monitored for infection and illness. Incidence of malaria episodes, molecular force of blood-stage infections ( mol FOB) and population-averaged prevalence of infections were compared across the cohorts to investigate the impact of intensified control in young children and the key risk factors for malaria infection and illness in 2013. Between 2006 and 2008, P. falciparum infection prevalence, mol FOB, and clinical malaria episodes reduced by 47%, 59% and 69%, respectively, and a further 49%, 29% and 75% from 2008 to 2013 (prevalence 41.6% to 22.1% to 11.2% mol FOB: 3.4 to 1.4 to 1.0 clones/child/year clinical episodes incidence rate (IR) 2.6 to 0.8 to IR 0.2 episodes/child/year). P. vivax clinical episodes declined at rates comparable to P. falciparum between 2006, 2008 and 2013 (IR 2.5 to 1.1 to 0.2), while P. vivax mol FOB (2006, 9.8 2008, 12.1) and prevalence (2006, 59.6% 2008, 65.0%) remained high in 2008. However, in 2013, P. vivax mol FOB (1.2) and prevalence (19.7%) had also substantially declined. In 2013, 89% of P. falciparum and 93% of P. vivax infections were asymptomatic, 62% and 47%, respectively, were sub-microscopic. Area of residence was the major determinant of malaria infection and illness. Intensified vector control and routine case management had a differential impact on rates of P. falciparum and P. vivax infections but not clinical malaria episodes in young children. This suggests comparable reductions in new mosquito-derived infections but a delayed impact on P. vivax relapsing infections due to a previously acquired reservoir of hypnozoites. This demonstrates the need to strengthen implementation of P. vivax radical cure to maximise impact of control in co-endemic areas. The high heterogeneity of malaria in 2013 highlights the importance of surveillance and targeted interventions to accelerate towards elimination.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.MEEGID.2014.04.010
Abstract: In placental malaria (PM), sequestration of infected erythrocytes in the placenta is mediated by an interaction between VAR2CSA, a Plasmodium falciparum protein expressed on erythrocytes, and chondroitin sulfate A (CSA) on syncytiotrophoblasts. Recent works have identified ID1-DBL2Xb as the minimal CSA-binding region within VAR2CSA able to induce strong protective immunity, making it the leading candidate for the development of a vaccine against PM. Assessing the existence of population differences in the distribution of ID1-DBL2Xb polymorphisms is of paramount importance to determine whether geographic ersity must be considered when designing a candidate vaccine based on this fragment. In this study, we examined patterns of sequence variation of ID1-DBL2Xb in a large collection of P. falciparum field isolates (n=247) from different malaria-endemic areas, including Africa (Benin, Senegal, Cameroon and Madagascar), Asia (Cambodia), Oceania (Papua New Guinea), and Latin America (Peru). Detection of variants and estimation of their allele frequencies were performed using next-generation sequencing of DNA pools. A considerable amount of variation was detected along the whole gene segment, suggesting that several allelic variants may need to be included in a candidate vaccine to achieve broad population coverage. However, most sequence variants were common and extensively shared among worldwide parasite populations, demonstrating long term persistence of those polymorphisms, probably maintained through balancing selection. Therefore, a vaccine mixture including such stable antigen variants will be putatively applicable and efficacious in all world regions where malaria occurs. Despite similarity in ID1-DBL2Xb allele repertoire across geographic areas, several peaks of strong population differentiation were observed at specific polymorphic loci, pointing out putative targets of humoral immunity subject to positive immune selection.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2011
Location: Australia
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alyssa Barry.