ORCID Profile
0000-0002-2971-5136
Current Organisations
Westmead Institute for Medical Research
,
Institute of Tropical Medicine Antwerp
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Publisher: European Centre for Disease Control and Prevention (ECDC)
Date: 21-04-2022
DOI: 10.2807/1560-7917.ES.2022.27.16.2100724
Abstract: We report an outbreak investigation of two fatal cases of autochthonous Plasmodium falciparum malaria that occurred in Belgium in September 2020. Various hypotheses of the potential source of infection were investigated. The most likely route of transmission was through an infectious exotic Anopheles mosquito that was imported via the international airport of Brussels or the military airport Melsbroek and infected the cases who lived at 5 km from the airports. Based on genomic analysis of the parasites collected from the two cases, the most likely origin of the Plasmodium was Gabon or Cameroon. Further, the parasites collected from the two Belgian patients were identical by descent, which supports the assumption that the two infections originated from the bite of the same mosquito, during interrupted feeding. Although airport malaria remains a rare event, it has significant implications, particularly for the patient, as delayed or missed diagnosis of the cause of illness often results in complications and mortality. Therefore, to prevent such severe or fatal outcomes, we suggest a number of public health actions including increased awareness among health practitioners, especially those working in the vicinity of airports, and increased surveillance of exotic mosquito species at airports.
Publisher: Cold Spring Harbor Laboratory
Date: 11-12-2020
DOI: 10.1101/2020.12.10.20244707
Abstract: Dysregulated immune response is a key driver of disease progression in sepsis and known to be associated with impaired cellular metabolism. This association has been studied mostly in the late stage sepsis patients. Here, we investigate whether such impairment in cellular metabolism is present in uncomplicated infection patients who do not develop sepsis. Forty sepsis (fulfilled Sepsis-3 criteria) and 27 uncomplicated infection patients were recruited from the emergency department along with 20 healthy volunteers. Whole blood was collected for measurement of gene expression, cytokine levels and cellular metabolic functions (including mitochondrial respiration, oxidative stress and apoptosis). Our analysis revealed the impairment of mitochondrial respiration in uncomplicated infection and sepsis patients (p value .05), with greater degree of impairment noted in the established sepsis. The impairment was significantly correlated with increased mitochondrial oxidative stress level the latter was increased in uncomplicated infection and more so in established sepsis patients. Further analysis revealed that the oxidative stress level correlated significantly with cytokine level (tumor necrosis factor-α) and gene expression levels (CYCS, TP53, SLC24A24 and TSPO). These findings suggest that impaired immune cell metabolism is present in infection patients without presenting sepsis, thereby opening potential window for early diagnosis and intervention (e.g. antioxidant therapy) in such patients.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2018
Publisher: Cold Spring Harbor Laboratory
Date: 24-04-0005
DOI: 10.1101/306860
Abstract: Longitudinal tracking of in idual Plasmodium falciparum strains in multi-clonal infections is essential for investigating infection dynamics of malaria. The traditional genotyping techniques did not permit tracking changes in in idual clone density during persistent natural infections. Amplicon deep sequencing (Amp-Seq) offers a tool to address this knowledge gap. The sensitivity of Amp-Seq for relative quantification of clones was investigated using three molecular markers, ama1-D2, ama1-D3, and cpmp. Amp-Seq and length-polymorphism based genotyping were compared for their performance in following minority clones in longitudinal s les from Papua New Guinea. Amp-Seq markers were superior to length-polymorphic marker msp2 in detecting minority clones (sensitivity Amp-Seq: 95%, msp2: 85%). Multiplicity of infection (MOI) by Amp-Seq was 2.32 versus 1.73 for msp2. The higher sensitivity had no effect on estimates of force of infection because missed minority clones were detected in preceding or succeeding bleeds. In idual clone densities were tracked longitudinally by Amp-Seq despite MOI , thus providing an additional parameter for investigating malaria infection dynamics. Amp-Seq based genotyping of longitudinal s les improves detection of minority clones and estimates of MOI. Amp-Seq permits tracking of clone density over time to study clone competition or the dynamics of specific, i.e. resistance-associated genotypes.
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: Elsevier BV
Date: 10-2018
Publisher: Frontiers Media SA
Date: 11-08-2022
DOI: 10.3389/FCIMB.2022.953187
Abstract: Although the power of genetic surveillance tools has been acknowledged widely, there is an urgent need in malaria endemic countries for feasible and cost-effective tools to implement in national malaria control programs (NMCPs) that can generate evidence to guide malaria control and elimination strategies, especially in the case of Plasmodium vivax . Several genetic surveillance applications (‘use cases’) have been identified to align research, technology development, and public health efforts, requiring different types of molecular markers. Here we present a new highly-multiplexed deep sequencing assay (Pv AmpliSeq). The assay targets the 33-SNP vivaxGEN-geo panel for country-level classification, and a newly designed 42-SNP within-country barcode for analysis of parasite dynamics in Vietnam and 11 putative drug resistance genes in a highly multiplexed NGS protocol with easy workflow, applicable for many different genetic surveillance use cases. The Pv AmpliSeq assay was validated using: 1) isolates from travelers and migrants in Belgium, and 2) routine collections of the national malaria control program at sentinel sites in Vietnam. The assay targets 229 licons and achieved a high depth of coverage (mean 595.7 ± 481) and high accuracy (mean error-rate of 0.013 ± 0.007). P. vivax parasites could be characterized from dried blood spots with a minimum of 5 parasites/µL and 10% of minority-clones. The assay achieved good spatial specificity for between-country prediction of origin using the 33-SNP vivaxGEN-geo panel that targets rare alleles specific for certain countries and regions. A high resolution for within-country ersity in Vietnam was achieved using the designed 42-SNP within-country barcode that targets common alleles (median MAF 0.34, range 0.01-0.49. Many variants were detected in (putative) drug resistance genes, with different predominant haplotypes in the pvmdr1 and pvcrt genes in different provinces in Vietnam. The capacity of the assay for high resolution identity-by-descent (IBD) analysis was demonstrated and identified a high rate of shared ancestry within Gia Lai Province in the Central Highlands of Vietnam, as well as between the coastal province of Binh Thuan and Lam Dong. Our approach performed well in geographically differentiating isolates at multiple spatial scales, detecting variants in putative resistance genes, and can be easily adjusted to suit the needs in other settings in a country or region. We prioritize making this tool available to researchers and NMCPs in endemic countries to increase ownership and ensure data usage for decision-making and malaria policy.
Publisher: Frontiers Media SA
Date: 30-09-2022
DOI: 10.3389/FCIMB.2022.1011692
Abstract: The Plasmodium vivax reticulocyte invasion process is still poorly understood, with only a few receptor-ligand interactions identified to date. In iduals with the Southeast Asian ovalocytosis (SAO) phenotype have a deletion in the band 3 protein on the surface of erythrocytes, and are reported to have a lower incidence of clinical P. vivax malaria. Based on this observation, band 3 has been put forward as a receptor for P. vivax invasion, although direct proof is still lacking. In this study, we combined functional ex vivo invasion assays and transcriptome sequencing to uncover a band 3–mediated invasion pathway in P. vivax and potential band 3 ligands. Invasion by P. vivax field isolates was 67%-71% lower in SAO reticulocytes compared with non-SAO reticulocytes. Reticulocyte invasion was decreased by 40% and 27%-31% when blocking with an anti-band 3 polyclonal antibody and a PvTRAg38 peptide, respectively. To identify new band 3 receptor candidates, we mRNA-sequenced schizont-stage isolates used in the invasion assays, and observed high transcriptional variability in multigene and invasion-related families. Transcriptomes of isolates with low or high dependency on band 3 for invasion were compared by differential expression analysis, which produced a list of band 3 ligand candidates with high representation of PvTRAg genes. Our ex vivo invasion assays have demonstrated that band 3 is a P. vivax invasion receptor and confirm previous in vitro studies showing binding between PvTRAg38 and band 3, although the lower and variable inhibition levels observed suggest the involvement of other ligands. By coupling transcriptomes and invasion phenotypes from the same isolates, we identified a list of band 3 ligand candidates, of which the overrepresented PvTRAg genes are the most promising for future research.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2016
DOI: 10.1038/NCOMMS12757
Abstract: Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.
Publisher: Frontiers Media SA
Date: 05-01-2023
DOI: 10.3389/FIMMU.2022.1060438
Abstract: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 ( IFI27 ) in COVID-19 patients. We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For ex le, in the pandemic H1N1/09 influenza virus infection, IFI27- like genes were highly upregulated in the blood s les of severely infected patients. These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2017
Publisher: Oxford University Press (OUP)
Date: 19-09-2017
Publisher: European Respiratory Society (ERS)
Date: 06-2017
DOI: 10.1183/13993003.02098-2016
Abstract: Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers. In this study, we combined an integrated genomic analysis of 1071 in iduals with in vitro experiments using well-established infection models. We identified a single-gene biomarker, IFI27 , which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections. IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting its implementation may improve the diagnosis and management of respiratory infection.
Publisher: Elsevier
Date: 2008
Publisher: Springer Science and Business Media LLC
Date: 28-01-2015
Publisher: Informa UK Limited
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 02-09-2019
Publisher: Springer Science and Business Media LLC
Date: 19-10-2015
Publisher: American Society for Microbiology
Date: 13-04-2023
DOI: 10.1128/SPECTRUM.00960-22
Abstract: While the power of next-generation sequencing technologies to inform and guide malaria control programs has become broadly recognized, the integration of genomic data for operational incorporation into malaria surveillance remains a challenge in most countries where malaria is endemic. The main obstacles include limited infrastructure, limited access to high-throughput sequencing facilities, and the need for local capacity to run an in-country analysis of genomes at a large-enough scale to be informative for surveillance.
Publisher: Cold Spring Harbor Laboratory
Date: 02-10-2021
DOI: 10.1101/2021.09.29.21263834
Abstract: We report an outbreak investigation of two fatal cases of autochthonous Plasmodium falciparum that occurred in Belgium in September 2020. Various hypotheses of potential source of infection were investigated. Based on the collected information, the most likely route of transmission was through an infectious exotic Anopheles mosquito that arrived via the international airport of Brussels or the Military airport Melsbroek and infected the cases who lived at five kilometres from the airports. Based on a genomic analysis of the parasites collected from the two cases, the most likely origin of the Plasmodium was Gabon or Cameroon. Further, the parasites collected from the two Belgian patients were identical-by-descent, which supports the assumption that the two infections originated from the bite of the same mosquito, during an interrupted feeding. Despite these cases, airport malaria remains a rare event. Yet, it has significant implications, particularly for the patient, as delayed or missed diagnosis of the cause of illness often results in high rates of complications and mortality. Therefore, to prevent such severe or fatal outcomes, a number of public health actions are suggested including increased awareness among health practitioners especially those working in the vicinity of airports and increased surveillance of exotic mosquito species at airports.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2018
Publisher: American Society of Tropical Medicine and Hygiene
Date: 08-2012
Publisher: Public Library of Science (PLoS)
Date: 30-12-2014
Publisher: Cold Spring Harbor Laboratory
Date: 24-10-2019
DOI: 10.1101/817320
Abstract: Monitoring the genetic structure of malaria parasite populations has been proposed as a novel and sensitive approach to quantify the impact of malaria control and elimination efforts. Here we describe the first population genetic analysis of sympatric Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) populations following nationwide distribution of long-lasting insecticide treated nets (LLIN) in Papua New Guinea (PNG). Parasite isolates from serial cross-sectional studies pre-(2005-6) and post-LLIN (2010-2014) were genotyped using microsatellite markers. Despite parasite prevalence declining substantially in these communities (East Sepik: Pf =54.9-8.5%, Pv =35.7-5.6%, Madang: Pf =38.0-9.0%, Pv : 31.8-19.7%), genetically erse and intermixing parasite populations remained. P. falciparum ersity declined modestly post-LLIN relative to pre-LLIN (East Sepik: R s = 7.1-6.4, H e = 0.77-0.71 Madang: R s = 8.2-6.1, H e = 0.79-0.71). Unexpectedly, population structure present in pre-LLIN populations was lost post-LLIN, suggesting that more frequent human movement between provinces may have contributed to higher gene flow between provinces. P. vivax prevalence initially declined but increased again in one province, yet ersity remained high throughout the study period (East Sepik: R s =11.4-9.3, H e =0.83-0.80 Madang: R s =12.2-14.5, H e =0.85-0.88). Although genetic differentiation values increased between provinces over time, no significant population structure was observed at any time point. For both species, the emergence of clonal transmission and significant multilocus linkage disequilibrium (mLD) due to increased focal inbreeding post-LLIN was a strong indicator of impact on the parasite population using these markers. After eight years of intensive malaria control in PNG and substantial prevalence decline the impact on parasite population ersity and structure detectable by microsatellite genotyping was limited.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2018
Publisher: Elsevier BV
Date: 05-2022
Publisher: Wiley
Date: 16-10-2020
DOI: 10.1111/MEC.15654
Publisher: Public Library of Science (PLoS)
Date: 27-08-2021
DOI: 10.1371/JOURNAL.PNTD.0009672
Abstract: Understanding epidemiological variables affecting gametocyte carriage and density is essential to design interventions that most effectively reduce malaria human-to-mosquito transmission. Plasmodium falciparum and P . vivax parasites and gametocytes were quantified by qPCR and RT-qPCR assays using the same methodologies in 5 cross-sectional surveys involving 16,493 in iduals in Brazil, Thailand, Papua New Guinea, and Solomon Islands. The proportion of infections with detectable gametocytes per survey ranged from 44–94% for P . falciparum and from 23–72% for P . vivax . Blood-stage parasite density was the most important predictor of the probability to detect gametocytes. In moderate transmission settings (prevalence by qPCR %), parasite density decreased with age and the majority of gametocyte carriers were children. In low transmission settings (prevalence %), % of gametocyte carriers were adults. Per survey, 37–100% of all in iduals positive for gametocytes by RT-qPCR were positive by light microscopy for asexual stages or gametocytes (overall: P . falciparum 178/348, P . vivax 235/398). Interventions to reduce human-to-mosquito malaria transmission in moderate-high endemicity settings will have the greatest impact when children are targeted. In contrast, all age groups need to be included in control activities in low endemicity settings to achieve elimination. Detection of infections by light microscopy is a valuable tool to identify asymptomatic blood stage infections that likely contribute most to ongoing transmission at the time of s ling.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2019
DOI: 10.1038/S41598-019-39656-7
Abstract: Longitudinal tracking of in idual Plasmodium falciparum strains in multi-clonal infections is essential for investigating infection dynamics of malaria. The traditional genotyping techniques did not permit tracking changes in in idual clone density during persistent natural infections. Amplicon deep sequencing (Amp-Seq) offers a tool to address this knowledge gap. The sensitivity of Amp-Seq for relative quantification of clones was investigated using three molecular markers, ama 1 -D2, ama1 -D3, and cpmp . Amp-Seq and length-polymorphism based genotyping were compared for their performance in following minority clones in longitudinal s les from Papua New Guinea. Amp-Seq markers were superior to length-polymorphic marker msp 2 in detecting minority clones (sensitivity Amp-Seq: 95%, msp2: 85%). Multiplicity of infection (MOI) by Amp-Seq was 2.32 versus 1.73 for msp2 . The higher sensitivity had no effect on estimates of force of infection because missed minority clones were detected in preceding or succeeding bleeds. In idual clone densities were tracked longitudinally by Amp-Seq despite MOI 1, thus providing an additional parameter for investigating malaria infection dynamics. Amp-Seq based genotyping of longitudinal s les improves detection of minority clones and estimates of MOI. Amp-Seq permits tracking of clone density over time to study clone competition or the dynamics of specific, i.e. resistance-associated genotypes.
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: 13-11-2021
DOI: 10.1101/2021.11.12.21266245
Abstract: Molecular surveillance for malaria has great potential to support national malaria control programs (NMCPs). To bridge the gap between research and implementation, several applications (use cases) have been identified to align research, technology development, and public health efforts. For implementation at NMCPs, there is an urgent need for feasible and cost-effective tools. We designed a new highly-multiplexed deep sequencing assay (Pf AmpliSeq), compatible with benchtop sequencers, allowing for high accuracy sequencing at higher coverage and lower cost than WGS, targeting genomic regions of interest. The novelty of the assay is in its high number of targets multiplexed in one easy workflow, combining population genetic markers with 13 near full-length resistance genes, applicable for many different use cases. We provide a first proof-of-principle for hrp2 and hrp3 deletion detection using licon sequencing. Initial sequence data processing can be performed automatically, and subsequent variant analysis requires minimal bioinformatic skills using any tabulated data analysis program. The assay was validated with a retrospective s le collection (n = 254) from the Peruvian Amazon between 2003 and 2018. By combining phenotypic markers and a within-country 28-SNP-barcode, we were able to distinguish different lineages with multiple resistant ( dhfr/dhps/crt/mdr1 ) haplotypes and hrp2 and hrp3 deletions, increasing in recent years. We found no evidence suggesting the emergence of ART-resistance in Peru. These findings indicate a parasite population under drug pressure, but susceptible to current antimalarials, and demonstrates the added value of a highly multiplexed molecular tool to inform malaria strategies and surveillance systems. While the power of next generation sequencing technologies to inform and guide malaria control programs has become broadly recognized, integration of genomic data for operational incorporation into malaria surveillance remains a challenge in most malaria endemic countries. The main obstacles include limited infrastructure and accessibility to high-throughput sequencing facilities and the need for local capacity to run in-country analysis of genomes at a large enough scale to be informative for surveillance. In addition, there is a lack of standardized laboratory protocols and automated analysis pipelines to generate reproducible and timely results useful for relevant stakeholders. With our standardized laboratory and bioinformatic workflow, malaria genetic surveillance data can be readily generated by surveillance researchers and malaria control programs in endemic countries, increasing ownership and ensuring timely results for informed decision and policy-making.
Publisher: BMJ
Date: 2021
DOI: 10.1136/BMJOPEN-2020-044497
Abstract: Accurate triage is an important first step to effectively manage the clinical treatment of severe cases in a pandemic outbreak. In the current COVID-19 global pandemic, there is a lack of reliable clinical tools to assist clinicians to perform accurate triage. Host response biomarkers have recently shown promise in risk stratification of disease progression however, the role of these biomarkers in predicting disease progression in patients with COVID-19 is unknown. Here, we present a protocol outlining a prospective validation study to evaluate the biomarkers’ performance in predicting clinical outcomes of patients with COVID-19. This prospective validation study assesses patients infected with COVID-19, in whom blood s les are prospectively collected. Recruited patients include a range of infection severity from asymptomatic to critically ill patients, recruited from the community, outpatient clinics, emergency departments and hospitals. Study s les consist of peripheral blood s les collected into RNA-preserving (PAXgene/Tempus) tubes on patient presentation or immediately on study enrolment. Real-time PCR (RT-PCR) will be performed on total RNA extracted from collected blood s les using primers specific to host response gene expression biomarkers that have been previously identified in studies of respiratory viral infections. The RT-PCR data will be analysed to assess the diagnostic performance of in idual biomarkers in predicting COVID-19-related outcomes, such as viral pneumonia, acute respiratory distress syndrome or bacterial pneumonia. Biomarker performance will be evaluated using sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operating characteristic curve. This research protocol aims to study the host response gene expression biomarkers in severe respiratory viral infections with a pandemic potential (COVID-19). It has been approved by the local ethics committee with approval number 2020/ETH00886. The results of this project will be disseminated in international peer-reviewed scientific journals.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2011
Publisher: Springer Science and Business Media LLC
Date: 05-10-2018
Publisher: Wiley
Date: 02-04-2012
DOI: 10.1111/J.1365-3156.2012.02975.X
Abstract: To evaluate persistence of several Plasmodium antigens in pregnant women after treatment and compare diagnostics during treatment follow-up. Thirty-two pregnant women (N = 32) with confirmed malaria infection by a histidine-rich protein 2 (HRP2)-based rapid diagnostic test (RDT) and microscopy were followed for 28 days after artemisinin-based combination therapy (ACT). A Plasmodium lactate dehydrogenase (pLDH)-based RDT and two ELISAs based on the detection of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and haeme detoxification protein (HDP) were compared with each other and to RT-PCR at each visit. The mean visit number (95% confidence interval) on which the HRP2-based RDT was still positive after treatment was 3.4 (2.7-4.1) visits with some patients still positive at day 28. This is significantly later than the pLDH-based RDT [0.84 (0.55-1.1)], microscopy (median 1, range 1-3), DHFR-TS-ELISA [1.7 (1.1-2.3)] and RT-PCR (median 2, range 1-5) (P < 0.05), but not significantly later than HDP-ELISA [2.1 (1.6-2.7)]. Lower gravidity and higher parasite density at day 0 resulted in significantly longer positive results with most tests (P < 0.05). HRP2 can persist up to 28 days after ACT treatment therefore, this test is not suitable for treatment follow-up in pregnant women and can generate problems when using this test during intermittent preventive treatment (IPTp). DHFR-TS is less persistent than HRP2, making it a potentially interesting target for diagnosis.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/270756
Publisher: MDPI AG
Date: 28-01-2023
DOI: 10.3390/IJMS24032524
Abstract: Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed to understand how cellular metabolism contributes to COVID-19 outcomes. Metacore pathway enrichment analyses on differentially expressed genes (encoded by both mitochondrial and nuclear deoxyribonucleic acid (DNA)) involved in cellular metabolism, regulation of mitochondrial respiration and organization, and apoptosis, was performed on RNA sequencing (RNASeq) data from blood s les collected from healthy controls and patients with mild/moderate or severe COVID-19. Genes from the enriched pathways were analyzed by network analysis to uncover interactions among them and up- or downstream genes within each pathway. Compared to the mild/moderate COVID-19, the upregulation of a myriad of growth factor and cell cycle signaling pathways, with concomitant downregulation of interferon signaling pathways, were observed in the severe group. Matrix metallopeptidase 9 (MMP9) was found in five of the top 10 upregulated pathways, indicating its potential as therapeutic target against COVID-19. In summary, our data demonstrates aberrant activation of endocrine signaling in severe COVID-19, and its implication in immune and metabolic dysfunction.
Publisher: Authorea, Inc.
Date: 25-10-2023
Publisher: Springer Science and Business Media LLC
Date: 20-06-2019
DOI: 10.1038/S41598-019-45228-6
Abstract: Plasmodium vivax parasites preferentially invade reticulocyte cells in a multistep process that is still poorly understood. In this study, we used ex vivo invasion assays and population genetic analyses to investigate the involvement of complement receptor 1 (CR1) in P . vivax invasion. First, we observed that P . vivax invasion of reticulocytes was consistently reduced when CR1 surface expression was reduced through enzymatic cleavage, in the presence of naturally low-CR1-expressing cells compared with high-CR1-expressing cells, and with the addition of soluble CR1, a known inhibitor of P . falciparum invasion. Immuno-precipitation experiments with P . vivax Reticulocyte Binding Proteins showed no evidence of complex formation. In addition, analysis of CR1 genetic data for worldwide human populations with different exposure to malaria parasites show significantly higher frequency of CR1 alleles associated with low receptor expression on the surface of RBCs and higher linkage disequilibrium in human populations exposed to P . vivax malaria compared with unexposed populations. These results are consistent with a positive selection of low-CR1-expressing alleles in vivax-endemic areas. Collectively, our findings demonstrate that CR1 availability on the surface of RBCs modulates P . vivax invasion. The identification of new molecular interactions is crucial to guiding the rational development of new therapeutic interventions against vivax malaria.
Publisher: American Society for Microbiology
Date: 16-07-2021
DOI: 10.1128/AAC.00095-21
Abstract: Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most countries where malaria is endemic. Monitoring P. vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse.
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.
Location: Australia
Location: Netherlands
Location: Papua New Guinea
No related grants have been discovered for Eline Kattenberg.