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  • Journal article
    Pothin E, Ferguson NM, Drakeley CJ, Ghani ACet al., 2016,

    Estimating malaria transmission intensity from Plasmodium falciparum serological data using antibody density models

    , Malaria Journal, Vol: 15, ISSN: 1475-2875

    Background: Serological data are increasingly being used to monitor malaria transmission intensity and havebeen demonstrated to be particularly useful in areas of low transmission where traditional measures such as EIR andparasite prevalence are limited. The seroconversion rate (SCR) is usually estimated using catalytic models in whichthe measured antibody levels are used to categorize individuals as seropositive or seronegative. One limitationof this approach is the requirement to impose a fixed cut-off to distinguish seropositive and negative individuals.Furthermore, the continuous variation in antibody levels is ignored thereby potentially reducing the precision of theestimate.Methods: An age-specific density model which mimics antibody acquisition and loss was developed to make fulluse of the information provided by serological measures of antibody levels. This was fitted to blood-stage antibodydensity data from 12 villages at varying transmission intensity in Northern Tanzania to estimate the exposure rate asan alternative measure of transmission intensity.Results: The results show a high correlation between the exposure rate estimates obtained and the estimated SCRobtained from a catalytic model (r = 0.95) and with two derived measures of EIR (r = 0.74 and r = 0.81). Estimates ofexposure rate obtained with the density model were also more precise than those derived from catalytic models.Conclusion: This approach, if validated across different epidemiological settings, could be a useful alternative frameworkfor quantifying transmission intensity, which makes more complete use of serological data.

  • Journal article
    Baum J, Zuccala E, Satchwell T, Angrisano F, Tan YH, Wilson MC, Heesom KJet al., 2016,

    Quantitative phospho-proteomics reveals the Plasmodium merozoite triggers pre-invasion host kinase modification of the red cell cytoskeleton

    , Scientific Reports, Vol: 6, ISSN: 2045-2322

    The invasive blood-stage malaria parasite – the merozoite – induces rapid morphological changes to the target erythrocyte during entry. However, evidence for active molecular changes in the host cell that accompany merozoite invasion is lacking. Here, we use invasion inhibition assays, erythrocyte resealing and high-definition imaging to explore red cell responses during invasion. We show that although merozoite entry does not involve erythrocyte actin reorganisation, it does require ATP to complete the process. Towards dissecting the ATP requirement, we present an in depth quantitative phospho-proteomic analysis of the erythrocyte during each stage of invasion. Specifically, we demonstrate extensive increased phosphorylation of erythrocyte proteins on merozoite attachment, including modification of the cytoskeletal proteins beta-spectrin and PIEZO1. The association with merozoite contact but not active entry demonstrates that parasite-dependent phosphorylation is mediated by host-cell kinase activity. This provides the first evidence that the erythrocyte is stimulated to respond to early invasion events through molecular changes in its membrane architecture.

  • Journal article
    Nolan T, Crisanti A, 2016,

    DRIVING OUT MALARIA

    , Scientist, Vol: 31, Pages: 24-31
  • Journal article
    Griffi JT, Bhatt S, Sinka ME, Gething PW, Lynch M, Patouillard E, Shutes E, Newman RD, Alonso P, Cibulskis RE, Ghani ACet al., 2016,

    Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study

    , Lancet Infectious Diseases, Vol: 16, Pages: 465-472, ISSN: 1473-3099
  • Journal article
    Koch M, Baum J, 2016,

    The Mechanics of Malaria Parasite Invasion of the Human Erythrocyte - Towards a Reassessment of the Host Cell Contribution

    , Cellular Microbiology, Vol: 18, Pages: 319-329, ISSN: 1462-5822

    Despite decades of research, we still know little about the mechanics of Plasmodium host cell invasion. Fundamentally, while the essential or non-essential nature of different parasite proteins is becoming clearer, their actual function and how each comes together to govern invasion are poorly understood. Furthermore, in recent years an emerging world view is shifting focus away from the parasite actin–myosin motor being the sole force responsible for entry to an appreciation of host cell dynamics and forces and their contribution to the process. In this review, we discuss merozoite invasion of the erythrocyte, focusing on the complex set of pre-invasion events and how these might prime the red cell to facilitate invasion. While traditionally parasite interactions at this stage have been viewed simplistically as mediating adhesion only, recent work makes it apparent that by interacting with a number of host receptors and signalling pathways, combined with secretion of parasite-derived lipid material, that the merozoite may initiate cytoskeletal re-arrangements and biophysical changes in the erythrocyte that greatly reduce energy barriers for entry. Seen in this light Plasmodium invasion may well turn out to be a balance between host and parasite forces, much like that of other pathogen infection mechanisms.

  • Journal article
    Slater HC, Griffin JT, Ghani AC, Okell LCet al., 2016,

    Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

    , Malaria Journal, Vol: 15, ISSN: 1475-2875

    BACKGROUND: Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. METHODS: Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. RESULTS: Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7 % increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. CONCLUSION: Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

  • Journal article
    Riglar DT, Whitehead L, Cowman AF, Rogers KL, Baum Jet al., 2016,

    Localization-based imaging of malarial antigens during red cell entry reaffirms role for AMA1 but not MTRAP in invasion

    , Journal of Cell Science, Vol: 129, Pages: 228-242, ISSN: 1477-9137

    Microscopy-based localisation of proteins during malaria parasite invasion of the erythrocyte is widely used for tentative assignment of protein function. To date, however, imaging has been limited by the rarity of invasion events and poor resolution available, given micron size of the parasite, which leads to a lack of quantitative measures for definitive localisation. Here, using computational image analysis we have attempted to assign relative protein localisation during invasion using wide-field deconvolution microscopy. By incorporating three-dimensional information we present a detailed assessment of known parasite effectors predicted to function during entry but as yet untested or for which data is equivocal. Our method, longitudinal intensity profiling, resolves confusion surrounding localisation of apical membrane antigen (AMA1) at the merozoite-erythrocyte junction and predicts that the merozoite thrombospondin related anonymous protein (MTRAP) is unlikely to play a direct role in the mechanics of entry, an observation supported with additional biochemical evidence. This approach sets a benchmark for imaging of complex micron-scale events and cautions against simplistic interpretations of small numbers of representative images for assignment of protein function or prioritisation of candidates as therapeutic targets.

  • Journal article
    Hammond A, Galizi R, Kyrou K, Simoni A, Siniscalchi C, Katsanos D, Gribble M, Baker D, Marois E, Russell S, Burt A, Windbichler N, Crisanti A, Nolan Tet al., 2016,

    A CRISPR-Cas9 gene drive system-targeting female reproduction in the malaria mosquito vector Anopheles gambiae

    , Nature Biotechnology, Vol: 34, Pages: 78-83, ISSN: 1087-0156

    Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female-sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene drive constructs designed to target and edit each gene. For each targeted locus we observed a strong gene drive at the molecular level, with transmission rates to progeny of 91.4 to 99.6%. Population modeling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to suppress mosquito populations to levels that do not support malaria transmission.

  • Journal article
    Baum J, Olshina M, Baumann H, Willison Ket al., 2016,

    Plasmodium actin is incompletely folded by heterologous protein-folding machinery and likely requires the native Plasmodium chaperonin complex to enter a mature functional state

    , The FASEB Journal, Vol: 30, Pages: 405-416, ISSN: 0892-6638

    Actin filament turnover underpins several processes in the life cycle of the malaria parasite, Plasmodium falciparum. Polymerization and depolymerization are especially important for gliding motility, a substrate-dependent form of cell movement that underpins the protozoan parasite’s ability to disseminate and invade host cells. To date, given difficulties in extraction of native actins directly from parasites, much of our biochemical understanding of malarial actin has instead relied on recombinant protein extracted and purified from heterologous protein expression systems. Here, using in vitro transcription-translation methodologies and quantitative protein-binding assays, we explored the folding state of heterologously expressed P. falciparum actin 1 (PfACTI) with the aim of assessing the reliability of current recombinant-protein-based data. We demonstrate that PfACTI, when expressed in non-native systems, is capable of binding to and release from bacterial, yeast, and mammalian chaperonin complexes but appears to be incompletely folded. Characterization of the native Plasmodium folding machinery in silico, the chaperonin containing t-complex protein-1 complex, highlights key divergences between the different chaperonin systems that likely underpins this incomplete folded state. These results highlight the importance of characterizing actin’s folded state and raise concerns about the interpretation of actin polymerization kinetics based solely on protein derived from heterologous expression systems.—Olshina, M. A., Baumann, H., Willison, K. R., Baum, J. Plasmodium actin is incompletely folded by heterologous protein-folding machinery and likely requires the native Plasmodium chaperonin complex to enter a mature functional state.

  • Journal article
    Wu L, van den Hoogen LL, Slater H, Walker PGT, Ghani AC, Drakeley CJ, Okell LCet al., 2015,

    Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategies

    , Nature, Vol: 528, Pages: S86-S93, ISSN: 0028-0836

    The global burden of malaria has been substantially reduced over the past two decades. Future efforts to reduce malaria further will require moving beyond the treatment of clinical infections to targeting malaria transmission more broadly in the community. As such, the accurate identification of asymptomatic human infections, which can sustain a large proportion of transmission, is becoming a vital component of control and elimination programmes. We determined the relationship across common diagnostics used to measure malaria prevalence — polymerase chain reaction (PCR), rapid diagnostic test and microscopy — for the detection of Plasmodium falciparum infections in endemic populations based on a pooled analysis of cross-sectional data. We included data from more than 170,000 individuals comparing the detection by rapid diagnostic test and microscopy, and 30,000 for detection by rapid diagnostic test and PCR. The analysis showed that, on average, rapid diagnostic tests detected 41% (95% confidence interval = 26–66%) of PCR-positive infections. Data for the comparison of rapid diagnostic test to PCR detection at high transmission intensity and in adults were sparse. Prevalence measured by rapid diagnostic test and microscopy was comparable, although rapid diagnostic test detected slightly more infections than microscopy. On average, microscopy captured 87% (95% confidence interval = 74–102%) of rapid diagnostic test-positive infections. The extent to which higher rapid diagnostic test detection reflects increased sensitivity, lack of specificity or both, is unclear. Once the contribution of asymptomatic individuals to the infectious reservoir is better defined, future analyses should ideally establish optimal detection limits of new diagnostics for use in control and elimination strategies.

  • Journal article
    Slater HC, Ross A, Ouedraogo AL, White LJ, Nguon C, Walker PGT, Ngor P, Aguas R, Silal SP, Dondorp AM, La Barre P, Burton R, Sauerwein RW, Drakeley C, Smith TA, Bousema T, Ghani ACet al., 2015,

    Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies

    , Nature, Vol: 528, Pages: S94-S101, ISSN: 0028-0836

    Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polym

  • Journal article
    Penny MA, Verity RV, Bever C, Sauboin C, Galactionova K, Flasche S, White MT, Wenger EA, Van de Velde N, Pemberton-Ross P, Griffin JT, Smith TA, Eckhoff PA, Muhib F, Jit M, Ghani ACet al., 2015,

    Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models

    , The Lancet, Vol: 387, Pages: 367-375, ISSN: 0140-6736

    BackgroundThe phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings.MethodsWe compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5–17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10 year olds (PfPR2–10; range 3–65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2–10 per dose.FindingsIn regions with a PfPR2–10 of 10–65%, RTS,S/AS01 is predicted to avert a median of 93 940 (range 20 490–126 540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116 480 (31 450–160 410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100 000 fully vaccinated children. A positive impact is also predicted at a PfPR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–2

  • Journal article
    White MT, Verity R, Churcher TS, Ghani ACet al., 2015,

    Vaccine approaches to malaria control and elimination: Insights from mathematical models

    , Vaccine, Vol: 33, Pages: 7544-7550, ISSN: 1873-2518

    A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts.Several candidate vaccines targeting different stages ofthe malaria parasite’s lifecycle are currently underdevelopment, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection,having recently completed Phase III trials. Predicting the public health impact of a candidate malariavaccine requires using clinical trial data to estimate the vaccine’s efficacy profile—the initial efficacyfollowing vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacyprofile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematicalmodels.Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocyticvaccines and transmission-blocking vaccines from clinicaltrial data. In the case of RTS,S/AS01, model estimatesfrom Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection,with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waningover the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II orPhase III clinical trials so we review ongoing work investigating how a clinical trial might be designed toensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstratehow parameters estimated from clinical trials can be used to predict the impact of vaccination campaignson malaria using a mathematical model of malaria transmission

  • Journal article
    Chertow JH, Alkaitis MS, Nardone G, Ikeda AK, Cunnington AJ, Okebe J, Ebonyi AO, Njie M, Correa S, Jayasooriya S, Casals-Pascual C, Billker O, Conway DJ, Walther M, Ackerman Het al., 2015,

    Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

    , PLOS Pathogens, Vol: 11, ISSN: 1553-7366

    Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.

  • Journal article
    White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D, Adjei S, Agbenyega T, Ogutu B, Otieno L, Otieno W, Agnandji ST, Lell B, Kremsner P, Hoffman I, Martinson F, Kamthunzu P, Tinto H, Valea I, Sorgho H, Oneko M, Otieno K, Hamel MJ, Salim N, Mtoro A, Abdulla S, Aide P, Sacarlal J, Aponte JJ, Njuguna P, Marsh K, Bejon P, Riley EM, Ghani ACet al., 2015,

    Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

    , Lancet Infectious Diseases, Vol: 15, Pages: 1450-1458, ISSN: 1473-3099

    BackgroundThe RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.MethodsUsing data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.FindingsRTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and effi

  • Journal article
    Haase S, Zimmermann D, Olshina MA, Wilkinson M, Fisher F, Tan YH, Stewart RJ, Tonkin CJ, Wong W, Kovar DR, Baum Jet al., 2015,

    Disassembly activity of actin depolymerization factor (ADF) is associated with distinct cellular processes in apicomplexan parasites.

    , Molecular Biology of the Cell, Vol: 26, Pages: 3001-3012, ISSN: 1939-4586

    Proteins of the actin depolymerizing factor (ADF)/cofilin family have been shown to be crucial for the motility and survival of apicomplexan parasites. However, the mechanisms by which ADF proteins fulfill their function remains poorly understood. In this study we sought to investigate the comparative activities of ADF proteins from Toxoplasma gondii and Plasmodium falciparum, the human malaria parasite, using a conditional T. gondii ADF-knockout line complemented with ADF variants from either species. We show that P. falciparum ADF1 can fully restore native TgADF activity, demonstrating functional conservation between parasites. Strikingly, mutation of a key basic residue (Lys(72)), previously implicated in disassembly in PfADF1, had no detectable phenotypic effect on parasite growth, motility or development. In contrast, organelle segregation was severely impaired when complementing with a TgADF mutant lacking the corresponding residue (Lys(68)). Biochemical analyses of each ADF protein confirmed the reduced ability of lysine mutants to mediate actin depolymerization via filament disassembly though not severing, in contrast to previous reports. These data suggest that actin filament disassembly is essential for apicomplexan parasite development but not for motility as well as pointing to genus-specific coevolution between ADF proteins and their native actin.

  • Journal article
    Cairns ME, Walker PGT, Okell LC, Griffin JT, Garske T, Asante KP, Owusu-Agyei S, Diallo D, Dicko A, Cisse B, Greenwood BM, Chandramohan D, Ghani AC, Milligan PJet al., 2015,

    Seasonality in malaria transmission: implications for case-management with long-acting artemisinin combination therapy in sub-Saharan Africa

    , Malaria Journal, Vol: 14, ISSN: 1475-2875

    Background: Long-acting artemisinin-based combination therapy (LACT) offers the potential to prevent recurrentmalaria attacks in highly exposed children. However, it is not clear where this advantage will be most important, anddeployment of these drugs is not rationalized on this basis.Methods: To understand where post-treatment prophylaxis would be most beneficial, the relationship betweenseasonality, transmission intensity and the interval between malaria episodes was explored using data from six cohortstudies in West Africa and an individual-based malaria transmission model. The total number of recurrent malariacases per 1000 child-years at risk, and the fraction of the total annual burden that this represents were estimated forsub-Saharan Africa.Results: In settings where prevalence is less than 10 %, repeat malaria episodes constitute a small fraction of thetotal burden, and few repeat episodes occur within the window of protection provided by currently available drugs.However, in higher transmission settings, and particularly in high transmission settings with highly seasonal transmis‑sion, repeat malaria becomes increasingly important, with up to 20 % of the total clinical burden in children estimatedto be due to repeat episodes within 4 weeks of a prior attack.Conclusion: At a given level of transmission intensity and annual incidence, the concentration of repeat malariaepisodes in time, and consequently the protection from LACT is highest in the most seasonal areas. As a result, thedegree of seasonality, in addition to the overall intensity of transmission, should be considered by policy makers whendeciding between ACT that differ in their duration of post-treatment prophylaxis.

  • Journal article
    Olshina MA, Angrisano F, Marapana DS, Riglar DT, Bane K, Wong W, Catimel B, Yin MX, Holmes AB, Frischknecht F, Kovar DR, Baum JACOBet al., 2015,

    Plasmodium falciparum coronin organizes arrays of parallel actin filaments potentially guiding directional motility in invasive malaria parasites

    , Malaria Journal, Vol: 14, ISSN: 1475-2875

    BackgroundGliding motility in Plasmodium parasites, the aetiological agents of malaria disease, is mediated by an actomyosin motor anchored in the outer pellicle of the motile cell. Effective motility is dependent on a parasite myosin motor and turnover of dynamic parasite actin filaments. To date, however, the basis for directional motility is not known. Whilst myosin is very likely orientated as a result of its anchorage within the parasite, how actin filaments are orientated to facilitate directional force generation remains unexplained. In addition, recent evidence has questioned the linkage between actin filaments and secreted surface antigens leaving the way by which motor force is transmitted to the extracellular milieu unknown. Malaria parasites possess a markedly reduced repertoire of actin regulators, among which few are predicted to interact with filamentous (F)-actin directly. One of these, PF3D7_1251200, shows strong homology to the coronin family of actin-filament binding proteins, herein referred to as PfCoronin.MethodsHere the N terminal beta propeller domain of PfCoronin (PfCor-N) was expressed to assess its ability to bind and bundle pre-formed actin filaments by sedimentation assay, total internal reflection fluorescence (TIRF) microscopy and confocal imaging as well as to explore its ability to bind phospholipids. In parallel a tagged PfCoronin line in Plasmodium falciparum was generated to determine the cellular localization of the protein during asexual parasite development and blood-stage merozoite invasion.ResultsA combination of biochemical approaches demonstrated that the N-terminal beta-propeller domain of PfCoronin is capable of binding F-actin and facilitating formation of parallel filament bundles. In parasites, PfCoronin is expressed late in the asexual lifecycle and localizes to the pellicle region of invasive merozoites before and during erythrocyte entry. PfCoronin also associates strongly with membranes within the cell, likely medi

  • Journal article
    Wilson DW, Goodman CD, Sleebs BE, Weiss GE, de Jong NWM, Angrisano F, Langer C, Baum J, Crabb BS, Gilson PR, McFadden GI, Beeson JGet al., 2015,

    Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum

    , BMC Biology, Vol: 13, ISSN: 1741-7007

    Background: Malaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessibleto inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarialagents act against host cell invasion.Results: Here, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill humanmalaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of redblood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidencedemonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent ofits inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drugwith multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasioninhibitors than parent compounds, offering promise for development of this novel antimalarial strategy.Conclusions: Safe and effective macrolide antibiotics with dual modalities could be developed to combat malariaand reduce the parasite’s options for resistance.

  • Journal article
    Walker PGT, White MT, Griffin JT, Reynolds A, Ferguson NM, Ghani ACet al., 2015,

    Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis

    , Lancet Infectious Diseases, Vol: 15, Pages: 825-832, ISSN: 1473-3099

    BackgroundThe ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease.MethodsWe estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand.FindingsIf malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43–49) in Guinea, 88% (83–93) in Sierra Leone, and 140% (135–147) in Liberia in 2014. This increase is equivalent to 3·5 million (95% credible interval 2·6 million to 4·9 million) additional untreated cases, with 10 900 (5700–21 400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria.InterpretationThese findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems.

  • Journal article
    Cunnington A, Orf K, 2015,

    Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection

    , Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X

    Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterised by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defence mechanisms, including macrophage dysfunction, neutrophil dysfunction and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.

  • Journal article
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