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  • Journal article
    Suh E, Grossman MK, Waite JL, Dennington NL, Sherrard-Smith E, Churcher TS, Thomas MBet al., 2020,

    The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria

    , Nature Ecology and Evolution, Vol: 4, Pages: 940-951, ISSN: 2397-334X

    Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how the timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite Plasmodium falciparum. In laboratory experiments, we found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures, there was a significant increase in competence for mosquitoes feeding in the evening (18:00), and a significant reduction in competence for those feeding in the morning (06:00), relative to those feeding at midnight (00:00). These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for malaria prevalence, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate that the interaction of temperature and feeding behaviour could be a major ecological determinant of the vectorial capacity of malaria mosquitoes.

  • Journal article
    Saunders CN, Cota E, Baum J, Tate EWet al., 2020,

    Peptide probes for Plasmodium falciparum MyoA tail interacting protein (MTIP): exploring the druggability of the malaria parasite motor complex

    , ACS Chemical Biology, Vol: 15, Pages: 1313-1320, ISSN: 1554-8929

    Malaria remains an endemic tropical disease, and the emergence of Plasmodium falciparum parasites resistant to current front-line medicines means that new therapeutic targets are required. The Plasmodium glideosome is a multiprotein complex thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Here, we report the design and development of improved peptide-based probes for the anchor point of MyoA, the P. falciparum MyoA tail interacting protein (PfMTIP). These probes combine low nanomolar binding affinity with significantly enhanced cell penetration and demonstrable competitive target engagement with native PfMTIP through a combination of Western blot and chemical proteomics. These results provide new insights into the potential druggability of the MTIP/MyoA interaction and a basis for the future design of inhibitors.

  • Journal article
    Monroe A, Moore S, Okumu F, Kiware S, Lobo NF, Koenker H, Sherrard-Smith E, Gimnig J, Killeen GFet al., 2020,

    Methods and indicators for measuring patterns of human exposure to malaria vectors

    , Malaria Journal, Vol: 19, Pages: 1-14, ISSN: 1475-2875

    BackgroundEffective targeting and evaluation of interventions that protect against adult malaria vectors requires an understanding of how gaps in personal protection arise. An improved understanding of human and mosquito behaviour, and how they overlap in time and space, is critical to estimating the impact of insecticide-treated nets (ITNs) and determining when and where supplemental personal protection tools are needed. Methods for weighting estimates of human exposure to biting Anopheles mosquitoes according to where people spend their time were first developed over half a century ago. However, crude indoor and outdoor biting rates are still commonly interpreted as indicative of human-vector contact patterns without any adjustment for human behaviour or the personal protection effects of ITNs.Main textA small number of human behavioural variables capturing the distribution of human populations indoors and outdoors, whether they are awake or asleep, and if and when they use an ITN over the course of the night, can enable a more accurate representation of human biting exposure patterns. However, to date no clear guidance is available on what data should be collected, what indicators should be reported, or how they should be calculated. This article presents an integrated perspective on relevant indicators of human-vector interactions, the critical entomological and human behavioural data elements required to quantify human-vector interactions, and recommendations for collecting and analysing such data.ConclusionsIf collected and used consistently, this information can contribute to an improved understanding of how malaria transmission persists in the context of current intervention tools, how exposure patterns may change as new vector control tools are introduced, and the potential impact and limitations of these tools. This article is intended to consolidate understanding around work on this topic to date and provide a consistent framework for building upon it. Ad

  • Journal article
    Amulic B, Moxon C, Cunnington A, 2020,

    A more granular view of neutrophils in malaria

    , Trends in Parasitology, Vol: 36, Pages: 501-503, ISSN: 0169-4758

    Neutrophils are abundant innate immune cells with crucial roles in immunity and vascular inflammation. Recent evidence indicates that neutrophils have a dual role in malaria, contributing to both pathogenesis and control of Plasmodium. We discuss emerging mechanisms behind these opposing functions and identify key outstanding questions.

  • Journal article
    Llora-Batlle O, Michel-Todo L, Witmer K, Toda H, Fernandez-Becerra C, Baum J, Cortes Aet al., 2020,

    Conditional expression of PfAP2-G for controlled massive sexual conversion in Plasmodium falciparum

    , SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548
  • Journal article
    Suh E, Grossman M, Waite J, Dennington N, Sherrard-Smith E, Churcher T, Thomas Met al., 2020,

    The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria

    , Nature Ecology and Evolution, ISSN: 2397-334X

    Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite, Plasmodium falciparum . We found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures there was a significant increase in competence for mosquitoes feeding in the evening, and a significant reduction in competence for those feeding in the morning, relative to those feeding at midnight. These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for disease endemicity, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate the interaction of temperature and feeding behaviour to be a major ecological determinant of the vectorial capacity of malaria mosquitoes.

  • Report
    Sherrard-Smith E, Hogan A, Hamlet A, Watson OJ, Whittaker C, Winskill P, Verity R, Lambert B, Cairns M, Okell L, Slater H, Ghani A, Walker P, Churcher T, Imperial College COVID19 response teamet al., 2020,

    Report 18: The potential public health impact of COVID-19 on malaria in Africa.

    The COVID-19 pandemic is likely to severely interrupt health systems in Sub-Saharan Africa (SSA) over the coming weeks and months. Approximately 90% of malaria deaths occur in this region of the world, with an estimated 380,000 deaths from malaria in 2018. Much of the gain made in malaria control over the last decade has been due to the distribution of long-lasting insecticide treated nets (LLINs). Many SSA countries planned to distribute these in 2020. We used COVID-19 and malaria transmission models to understand the likely impact that disruption to these distributions, alongside other core health services, could have on the malaria burden. Results indicate that if all malaria-control activities are highly disrupted then the malaria burden in 2020 could more than double that in the previous year, resulting in large malaria epidemics across the region. These will depend on the course of the COVID-19 epidemic and how it interrupts local health system. Our results also demonstrate that it is essential to prioritise the LLIN distributions either before or as soon as possible into local COVID-19 epidemics to mitigate this risk. Additional planning to ensure other malaria prevention activities are continued where possible, alongside planning to ensure basic access to antimalarial treatment, will further minimise the risk of substantial additional malaria mortality.

  • Journal article
    Wilkinson MD, Lai H-E, Freemont PS, Baum Jet al., 2020,

    A biosynthetic platform for antimalarial drug discovery

    , Antimicrobial Agents and Chemotherapy, Vol: 64, Pages: 1-9, ISSN: 0066-4804

    Advances in synthetic biology have enabled production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its non-native synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially-derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially-derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and resistant patient isolates, confirming the potential utility of this drug as an antimalarial. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The demonstrated varied activity of each derivative against asexual parasite growth points to potential for further development of violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behaviour in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery with potential applications in future high-throughput drug screening with otherwise chemically-intractable natural products.

  • Journal article
    Rueda-Zubiaurre A, Yahiya S, Fischer O, Hu X, Saunders C, Sharma S, Straschil U, Shen J, Tate EW, Delves M, Baum J, Barnard A, Fuchter MJet al., 2020,

    Structure-activity relationship studies of a novel class of transmission blocking antimalarials targeting male gametes.

    , Journal of Medicinal Chemistry, Vol: 63, Pages: 2240-2262, ISSN: 0022-2623

    Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.

  • Journal article
    Okell L, Bretscher MT, Dahal P, Griffin J, stepniewska K, Bassat Q, Baudin E, D'Alessandro U, Djimde A, Dorsey G, Espie E, Fofana B, Gonzalez R, Juma E, Karema C, Lasry E, Lell B, Lima N, Menendez C, Mombo-Ngoma G, Moreira C, Nikiema F, Ouedraogo J, Staedke S, Tinto H, Valea I, Yeka A, Ghani A, Guerin Pet al., 2020,

    The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data

    , BMC Medicine, Vol: 18, Pages: 1-17, ISSN: 1741-7015

    Background: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programmes combined with sulfadoxine-pyrimethamine. Whilst artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n=4214 individuals). The time to PCR-confirmed re-infection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to re-infection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to re-infection in multivariate models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~2-fold longer protection than AL. Conversely at a higher prevalence of 86Y and 76T mutant parasites (>80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protec

  • Journal article
    Suen HM, Pasvol G, Cunnington A, 2020,

    Clinical and laboratory features associated with serum phosphate concentrations in malaria and other febrile illnesses

    , Malaria Journal, Vol: 19, ISSN: 1475-2875

    BackgroundHypophosphatemia is common in severe infections including malaria. Previous studies suggested that serum phosphate concentrations correlate with temperature, but it is unclear whether the type of infection and other factors occurring during infection influence this association. Here relationships were investigated between serum phosphate levels, cause of fever, demographic, clinical and laboratory parameters.MethodsAnonymized data were analysed from 633 adults with malaria or other febrile illness admitted to Northwick Park Hospital, London, UK. Univariable and multivariable generalized linear model analyses were performed to examine associations with serum phosphate levels. Interaction terms were included to investigate whether cause of fever (malaria vs other illness), malaria parasite species, or malaria severity influenced the association of other variables with phosphate.ResultsHypophosphatemia was common in subjects with malaria (211/542 (39%)), and in other febrile illnesses (24/91 (26%)), however median phosphate levels did not differ significantly by diagnostic group, parasite species or severity of malaria. In all analyses, there were highly significant negative associations between serum phosphate and axillary temperature, and positive associations between serum phosphate and platelet count. There were no significant interactions between these variables and cause of fever, parasite species or severity of illness. Sodium and potassium concentrations were associated with serum phosphate in subjects with malaria and when data from all subjects was combined.ConclusionSerum phosphate is consistently associated with temperature and platelet count in adults with diverse causes of fever. This may be a consequence of phosphate shifts from plasma into cells to support ATP generation for thermogenesis and platelet activation.

  • Journal article
    Patel H, Dunican C, Cunnington A, 2020,

    Predictors of outcome in childhood Plasmodium falciparum malaria

    , Virulence, Vol: 11, Pages: 199-221, ISSN: 2150-5594

    Plasmodium falciparum malaria is classified as either uncomplicated or severe, determining clinical management and providing a framework for understanding pathogenesis. Severe malaria in children is defined by the presence of one or more features associated with adverse outcome, but there is wide variation in the predictive value of these features. Here we review the evidence for the usefulness of these features, alone and in combination, to predict death and other adverse outcomes, and we consider the role that molecular biomarkers may play in augmenting this prediction. We also examine whether a more personalized approach to predicting outcome for specific presenting syndromes of severe malaria, particularly cerebral malaria, has the potential to be more accurate. We note a general need for better external validation in studies of outcome predictors and for the demonstration that predictors can be used to guide clinical management in a way that improves survival and long-term health.

  • Journal article
    Witmer K, Dahalan FA, Delves MJ, Yahiya S, Watson OJ, Straschil U, Chiwcharoen D, Sornboon B, Pukrittayakamee S, Pearson RD, Howick VM, Lawniczak MKN, White NJ, Dondorp AM, Okell LC, Ruecker A, Chotivanich K, Baum Jet al., 2020,

    Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

    <jats:title>ABSTRACT</jats:title><jats:p>Resistance to artemisinin combination therapy (ACT) in the <jats:italic>Plasmodium falciparum</jats:italic> parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed asexual parasite clearance in patients following ACT treatment, the phenotype can only spread geographically via the sexual cycle and subsequent transmission through the mosquito. Artemisinin and its derivatives (such as dihydroartemisinin, DHA) as well as killing the asexual parasite form are known to sterilize male, sexual-stage gametes from activation. Whether resistant parasites overcome this artemisinin-dependent sterilizing effect has not, however, been fully tested. Here, we analysed five <jats:italic>P. falciparum</jats:italic> clinical isolates from the Greater Mekong Subregion, each of which demonstrated delayed clinical clearance and carried known resistance-associated polymorphisms in the <jats:italic>Kelch13</jats:italic> gene (PfK13<jats:sup>var</jats:sup>). As well as demonstrating reduced sensitivity to artemisinin-derivates in <jats:italic>in vitro</jats:italic> asexual growth assays, certain PfK13<jats:sup>var</jats:sup> isolates also demonstrated a marked reduction in sensitivity to these drugs in an <jats:italic>in vitro</jats:italic> male gamete activation assay compared to a sensitive control. Importantly, the same reduction in sensitivity to DHA was observed when the most resistant isolate was assayed by standard membrane feeding assays using <jats:italic>Anopheles stephensi</jats:italic> mosquitoes. These results indicate that ACT use can favour resistant over sensitive parasite transmission. A selective advantage for resistant parasite transmission could also favour acquisition of further polymorphisms, such as mosquito host-specificity or antimalarial partne

  • Journal article
    Wang X, Wilkinson MD, Lin X, Ren R, Willison KR, Ivanov A, Baum J, Edel Jet al., 2020,

    Single-molecule nanopore sensing of actin dynamics and drug binding

    , Chemical Science, Vol: 11, Pages: 970-979, ISSN: 2041-6520

    Actin is a key protein in the dynamic processes within the eukaryotic cell. To date, methods exploring the molecular state of actin are limited to insights gained from structural approaches, providing a snapshot of protein folding, or methods that require chemical modifications compromising actin monomer thermostability. Nanopore sensing permits label-free investigation of native proteins and is ideally suited to study proteins such as actin that require specialised buffers and cofactors. Using nanopores, we determined the state of actin at the macromolecular level (filamentous or globular) and in its monomeric form bound to inhibitors. We revealed urea-dependent and voltage-dependent transitional states and observed unfolding process within which sub-populations of transient actin oligomers are visible. We detected, in real-time, filament-growth, and drug-binding at the single-molecule level demonstrating the promise of nanopores sensing for in-depth understanding of protein folding landscapes and for drug discovery.

  • Conference paper
    Unwin HJT, Sherrard-Smith E, Churcher TS, Ghani ACet al., 2020,

    MODELLING THE IMPACT OF PYRETHROID RESISTANCE ON PERSONAL PROTECTION AND THE MASS COMMUNITY EFFECT OF LONG-LASTING INSECTICIDE TREATED NETS

    , 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 187-187, ISSN: 0002-9637
  • Journal article
    Warszawski S, Dekel E, Campeotto J, Marshall J, Wright K, Lyth O, Knop N, Regev-Rudzki N, Baum J, Draper S, Higgins M, Fleishman Set al., 2020,

    Design of a basigin-mimicking inhibitor targeting the malaria invasion protein RH5

    , Proteins: Structure, Function, and Bioinformatics, Vol: 88, Pages: 187-195, ISSN: 0887-3585

    Many human pathogens use host cell-surface receptors to attach and invade cells. Often, thehost-pathogen interaction affinity is low, presenting opportunities to block invasion using asoluble, high-affinity mimic of the host protein. The Plasmodium falciparum reticulocyte-bindingprotein homolog 5 (RH5) provides an exciting candidate for mimicry: it is highly conserved andits moderate affinity binding to the human receptor basigin (KD≥1 μM) is an essential step inerythrocyte invasion by this malaria parasite. We used deep mutational scanning of a solublefragment of human basigin to systematically characterize point mutations that enhance basiginaffinity for RH5 and then used Rosetta to design a variant within the sequence space ofaffinity-enhancing mutations. The resulting seven-mutation design exhibited 2,500-fold higheraffinity (KD<1 nM) for RH5 with a very slow binding off rate (0.23 h-1) and reduced the effectivePlasmodium growth-inhibitory concentration by at least tenfold compared to human basigin. Thedesign provides a favorable starting point for engineering on-rate improvements that are likelyto be essential to reach therapeutically effective growth inhibition. Designed mimics may providetherapeutic advantages over antibodies, since the mimics bind to essential surfaces on the targetpathogen proteins, reducing the likelihood for the emergence of escape mutants

  • Journal article
    Murray GPD, Lissenden N, Jones J, Voloshin V, Toé KH, Sherrard-Smith E, Foster GM, Churcher TS, Parker JEA, Towers CE, NFalé S, Guelbeogo WM, Ranson H, Towers D, McCall PJet al., 2020,

    Barrier bednets target malaria vectors and expand the range of usable insecticides

    , Nature Microbiology, Vol: 5, Pages: 40-47, ISSN: 2058-5276

    Transmission of Plasmodium falciparum malaria parasites occurs when nocturnal Anopheles mosquito vectors feed on human blood. In Africa, where malaria burden is highest, bednets treated with pyrethroid insecticide were highly effective in preventing mosquito bites and reducing transmission, and essential to achieving unprecedented reductions in malaria until 2015 (ref. 1). Since then, progress has stalled2, and with insecticidal bednets losing efficacy against pyrethroid-resistant Anopheles vectors3,4, methods that restore performance are urgently needed to eliminate any risk of malaria returning to the levels seen before their widespread use throughout sub-Saharan Africa5. Here, we show that the primary malaria vector Anopheles gambiae is targeted and killed by small insecticidal net barriers positioned above a standard bednet in a spatial region of high mosquito activity but zero contact with sleepers, opening the way for deploying many more insecticides on bednets than is currently possible. Tested against wild pyrethroid-resistant A. gambiae in Burkina Faso, pyrethroid bednets with organophosphate barriers achieved significantly higher killing rates than bednets alone. Treated barriers on untreated bednets were equally effective, without significant loss of personal protection. Mathematical modelling of transmission dynamics predicted reductions in clinical malaria incidence with barrier bednets that matched those of ‘next-generation’ nets recommended by the World Health Organization against resistant vectors. Mathematical models of mosquito–barrier interactions identified alternative barrier designs to increase performance. Barrier bednets that overcome insecticide resistance are feasible using existing insecticides and production technology, and early implementation of affordable vector control tools is a realistic prospect.

  • Journal article
    van Lenthe M, van der Meulen R, Lassovski M, Ouabo A, Bakula E, Badio C, Cibenda D, Okell L, Piriou E, Grignard L, Lanke K, Rao B, Bousema T, Roper Cet al., 2019,

    Markers of sulfadoxine-pyrimethamine resistance in Eastern Democratic Republic of Congo; implications for malaria chemoprevention

    , Malaria Journal, Vol: 18, Pages: 1-9, ISSN: 1475-2875

    BackgroundSulfadoxine–pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap.MethodsDried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays.ResultsAcross populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5–25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3–87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7–47.2%). The dhfr I164L mutation was found in one sample.ConclusionsThe prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DR

  • Journal article
    Challenger J, Goncalves BP, Bradley J, Bruxvoort K, Tiono AB, Drakeley C, Bousema T, Ghani AC, Okell LCet al., 2019,

    How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study

    , BMJ Global Health, Vol: 4, ISSN: 2059-7908

    IntroductionArtemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicatedPlasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routinehealthcare settings, however, its effectiveness can be diminished by delayed access to treatmentand poor adherence. As well as affecting clinical outcomes, these factors can lead to increasedtransmission, which is the focus of this study.MethodsWe extend a within-host model of Plasmodium falciparum to include gametocytes, the parasiteforms responsible for onward transmission. The model includes a pharmacokineticpharmacodynamic model of AL, calibrated against both immature and mature gametocytes usingindividual-level patient data, to estimate the impact that delayed access and imperfect adherence totreatment can have on onward transmission of the parasite to mosquitoes.ResultsUsing survey data from 7 African countries to determine the time taken to acquire antimalarialsfollowing fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared to patients treated after 24 hours. Realistic adherence behaviour, based on datafrom a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold,compared to a perfectly-adherent cohort. This was driven largely by increased rates of treatmentfailure leading to chronic infection, rather than prolonged gametocytaemia in patients who haveslower, but still successful, clearance of parasites after imperfect adherence to treatment. Ourmodel estimated that the mean infectivity of untreated infections was 29-51 times higher than thatof treated infections (assuming perfect drug adherence), underlining the importance of improvingtreatment coverage.ConclusionUsing mathematical modelling, we quantify how delayed treatment and non-adherent treatmentcan increase transmission compared to prompt effective treatment. We also highlight thattransmission from the large proporti

  • Journal article
    Del Rosario M, Periz J, Pavlou G, Lyth O, Latorre-Barragan F, Das S, Pall GS, Stortz JF, Lemgruber L, Whitelaw JA, Baum J, Tardieux I, Meissner Met al., 2019,

    Apicomplexan F-actin is required for efficient nuclear entry during host cell invasion

    , EMBO REPORTS, Vol: 20, ISSN: 1469-221X
  • Journal article
    Malpartida-Cardenas K, Miscourides N, Rodriguez-Manzano J, Yu L-S, Moser N, Baum J, Georgiou Pet al., 2019,

    Quantitative and rapid Plasmodium falciparum malaria diagnosis and artemisinin-resistance detection using a CMOS Lab-on-Chip platform

    , Biosensors and Bioelectronics, Vol: 145, ISSN: 0956-5663

    Early and accurate diagnosis of malaria and drug-resistance is essential to effective disease management. Available rapid malaria diagnostic tests present limitations in analytical sensitivity, drug-resistance testing and/or quantification. Conversely, diagnostic methods based on nucleic acid amplification stepped forwards owing to their high sensitivity, specificity and robustness. Nevertheless, these methods commonly rely on optical measurements and complex instrumentation which limit their applicability in resource-poor, point-of-care settings. This paper reports the specific, quantitative and fully-electronic detection of Plasmodium falciparum, the predominant malaria-causing parasite worldwide, using a Lab-on-Chip platform developed in-house. Furthermore, we demonstrate on-chip detection of C580Y, the most prevalent single-nucleotide polymorphism associated to artemisinin-resistant malaria. Real-time non-optical DNA sensing is facilitated using Ion-Sensitive Field-Effect Transistors, fabricated in unmodified complementary metal-oxide-semiconductor (CMOS) technology, coupled with loop-mediated isothermal amplification. This work holds significant potential for the development of a fully portable and quantitative malaria diagnostic that can be used as a rapid point-of-care test.

  • Journal article
    Koch M, Cegla J, Jones B, Lu Y, Mallar Z, Blagborough A, Angrisano F, Baum Jet al., 2019,

    The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection

    , Malaria Journal, Vol: 18, ISSN: 1475-2875

    BackgroundMalaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes. Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests erythrocyte biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties demanding its interrogation as a potential mediator of resistance to merozoite invasion of the erythrocyte. MethodsBiophysical measurements of erythrocyte deformability by flicker spectroscopy were used to assess changes in erythrocyte bending modulus on forced integration of cholesterol and how these artificial changes affect invasion by human Plasmodium falciparum merozoites. To validate these observations in a natural context, either murine Plasmodium berghei or human Plasmodium falciparum merozoites were tested for their ability to invade erythrocytes from a hypercholesterolaemic mouse model or human clinical erythrocyte samples deriving from patients with a range of serum cholesterol concentrations, respectively. ResultsErythrocyte bending modulus (a measure of deformability) was shown to be markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. In an in vitro infection context, however, erythrocytes taken from hypercholesterolaemic mice or from human clinical samples with varying serum cholesterol levels showed little difference in their susceptibility to merozoite invasion. Explaining this, membrane cholesterol levels in both mouse and human hypercholesterolaemia erythrocytes were subsequently found to be no different from matched normal serum controls.ConclusionsBased on these observations, serum cholesterol does not appear to impact on erythrocyte susceptibility to merozoite entry. Indeed, no relationship between serum cholesterol and cholesterol content of the erythrocyte is apparent. This work, nonetheless, suggests that native p

  • Journal article
    Georgiadou A, Cunnington AJ, 2019,

    Shedding of the vascular endothelial glycocalyx - a common pathway to severe malaria?

    , Clinical Infectious Diseases, Vol: 69, Pages: 1721-1723, ISSN: 1058-4838
  • Journal article
    Satchwell TJ, Wright K, Haydn-Smith K, Sanchez-Roman Teran F, Moura P, Hawksworth J, Frayne J, Toye A, Baum Jet al., 2019,

    Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements

    , Nature Communications, Vol: 10, Pages: 1-9, ISSN: 2041-1723

    Investigatingthe role host erythrocyteproteins play in malaria infection is hampered by the genetic intractability of this anucleate cell. Here we report that reticulocytes derived through in vitro differentiation of an enucleation-competent immortalized erythroblast cell line (BEL-A) support both successful invasion and intracellular development of the malaria parasite Plasmodium falciparum. Using CRISPR-mediated gene knockout and subsequent complementation, we validate an essential role for the erythrocyte receptor basigin in P. falciparum invasion and, for the first time, demonstrate rescueby receptor re-expression.Successful invasion of reticulocytes complemented with a truncated mutant excludes a functional role for the basigincytoplasmic domain during invasion. Contrastingly, knockout of cyclophilin B, reported to participate in invasion and interact with basigin, did not impactinvasive susceptibility of reticulocytes.These data establish the use of reticulocytes derived from immortalized erythroblasts as a powerful model system to explore hypotheses regarding host receptor requirements for P. falciparum invasion.

  • Journal article
    Charani E, Cunnington AJ, Yousif AHA, Ahmed MS, Ahmed AEM, Babiker S, Bedri S, Buytaert W, Crawford MA, Elbashir MI, Elhag K, Elsiddig KE, Hakim N, Johnson MR, Miras AD, Swar MO, Templeton MR, Taylor-Robinson SDet al., 2019,

    In transition: current health challenges and priorities in Sudan

    , BMJ Global Health, Vol: 4:e001723, ISSN: 2059-7908

    A recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal, and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency, and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the UN sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.

  • Journal article
    Evans C, Fitzgerald F, Cunnington A, 2019,

    Review of UK malaria treatment guidelines 2016 (Public Health England Advisory Committee on Malaria Prevention)

    , ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION, Vol: 104, Pages: 218-220, ISSN: 1743-0585
  • Journal article
    Sherrard-Smith E, Skarp JE, Beale AD, Fornadel C, Norris LC, Moore SJ, Mihreteab S, Charlwood JD, Bhatt S, Winskill P, Griffin JT, Churcher TSet al., 2019,

    Mosquito feeding behavior and how it influences residual malaria transmission across Africa

    , Proceedings of the National Academy of Sciences, Vol: 116, Pages: 15086-15095, ISSN: 0027-8424

    The antimalarial efficacy of the most important vector control interventions—long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS)—primarily protect against mosquitoes’ biting people when they are in bed and indoors. Mosquito bites taken outside of these times contribute to residual transmission which determines the maximum effectiveness of current malaria prevention. The likelihood mosquitoes feed outside the time of day when LLINs and IRS can protect people is poorly understood, and the proportion of bites received outdoors may be higher after prolonged vector control. A systematic review of mosquito and human behavior is used to quantify and estimate the public health impact of outdoor biting across Africa. On average 79% of bites by the major malaria vectors occur during the time when people are in bed. This estimate is substantially lower than previous predictions, with results suggesting a nearly 10% lower proportion of bites taken at the time when people are beneath LLINs since the year 2000. Across Africa, this higher outdoor transmission is predicted to result in an estimated 10.6 million additional malaria cases annually if universal LLIN and IRS coverage was achieved. Higher outdoor biting diminishes the cases of malaria averted by vector control. This reduction in LLIN effectiveness appears to be exacerbated in areas where mosquito populations are resistant to insecticides used in bed nets, but no association was found between physiological resistance and outdoor biting. Substantial spatial heterogeneity in mosquito biting behavior between communities could contribute to differences in effectiveness of malaria control across Africa.

  • Journal article
    Baum J, Robert-Paginin J, Robblee J, Auguin D, Blake T, Bookwalter C, Krementsova E, Moussaoui D, Previs M, Jousset G, Trybus K, Houdusse Aet al., 2019,

    Plasmodium myosin a drives parasite invasion by an atypical force generating mechanism

    , Nature Communications, Vol: 10, ISSN: 2041-1723

    Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by Myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A from Plasmodium falciparum (PfMyoA) is critical for red blood cell invasion. Further, using a combination of X-ray crystallography, kinetics, and in vitro motility assays, we elucidate the non-canonical interactions that drive this motor’s function. We show that PfMyoA motor properties are tuned by heavy chain phosphorylation (Ser19), with unphosphorylated PfMyoA exhibiting enhanced ensemble force generation at the expense of speed. Regulated phosphorylation may therefore optimize PfMyoA for enhanced force generation during parasite invasion or for fast motility during dissemination. The three PfMyoA crystallographic structures presented here provide a blueprint for discovery of specific inhibitors designed to prevent parasite infection.

  • Journal article
    Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ, Ninis N, McCulloch M, Argent A, Buys H, Moxon CA, Best A, Nijman RG, Hoggart CJ, Levin M, Cunnington A, Wilson C, Nadel S, Lang H, Ninis N, McCulloch M, Argent A, Buys H, Moxon C, Best A, Nijman R, Hoggart Cet al., 2019,

    Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial

    , Lancet Respiratory Medicine, Vol: 7, Pages: 581-593, ISSN: 2213-2600

    BACKGROUND: Fluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry. METHODS: We developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593. FINDINGS: Increasing respiratory (odds ratio 1·09, 95% CI 1·07-1·11), neurological (1·26, 1·21-1·31), and cardiovascular scores (1·09, 1·05-1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20-0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76-2·06; p=0·0002) in mean base excess and increase o

  • Journal article
    Georgiadou A, Lee HJ, Walther M, van Beek A, Fitriani F, Wouters D, Kuijpers T, Nwakanma D, D'Alessandro U, Riley E, Otto T, Ghani A, Levin M, Coin L, Conway D, Bretscher M, Cunnington Aet al., 2019,

    Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions

    , Nature Microbiology, Vol: 4, Pages: 1592-1602, ISSN: 2058-5276

    During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in severe malaria cases, with severe anemia being more insidious than cerebral malaria. We predicted that parasite growth-inhibition was associated with platelet consumption, lower expression of CXCL10 and type-1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. Parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.

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