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  • Journal article
    Thompson H, Hogan A, Walker P, White M, Cunnington A, Ockenhouse C, Ghani Aet al., 2020,

    Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

    , Vaccine, Vol: 38, Pages: 7498-7507, ISSN: 0264-410X

    Anti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4–80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8–94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6–99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.

  • Journal article
    Eagon S, Hammill JT, Sigal M, Ahn KJ, Tryhorn JE, Koch G, Belanger B, Chaplan CA, Loop L, Kashtanova AS, Yniguez K, Lazaro H, Wilkinson SP, Rice AL, Falade MO, Takahashi R, Kim K, Cheung A, DiBernardo C, Kimball JJ, Winzeler EA, Eribez K, Mittal N, Gamo F-J, Crespo B, Churchyard A, García-Barbazán I, Baum J, Anderson MO, Laleu B, Guy RKet al., 2020,

    Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-b]pyridines.

    , J Med Chem, Vol: 63, Pages: 11902-11919

    Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4-b]pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc1.

  • Journal article
    Mousa A, Al-Taiar A, Anstey NM, Badaut C, Barber BE, Bassat Q, Challenger J, Cunnington AJ, Datta D, Drakeley C, Ghani AC, Gordeuk VR, Grigg MJ, Hugo P, John CC, Mayor A, Migot-Nabias F, Opoka RO, Pasvol G, Rees C, Reyburn H, Riley EM, Shah BN, Sitoe A, Sutherland CJ, Thuma PE, Unger SA, Viwami F, Walther M, Whitty CJM, William T, Okell LCet al., 2020,

    The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis

    , PLoS Medicine, Vol: 17, Pages: 1-28, ISSN: 1549-1277

    Background: Delay in receiving treatment for uncomplicated malaria is often reported to increase the risk of developing severe malaria, but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as “test-and-treat” policies administered by community health workers. We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with severe malaria.Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe P. falciparum malaria which included information on treatment delay, such as fever duration 12(inceptions to 22nd September 2017). Studies identified included five case-control and eight other observational clinical studies of severe and uncomplicated malaria cases. Risk of bias was assessed using the Newcastle–Ottawa scale and all studies were ranked as “Good”, scoring ≥7/10. Individual-patient data were pooled from thirteen studies of 3,989(94.1% aged <15 years)severe malaria patients and 5,780(79.6% aged <15 years)uncomplicated malaria cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen and Zambia. Definitions of severe malaria were standardised across studies to compare treatment delay in patients with uncomplicated malaria and different severe malaria phenotypes using age-adjusted mixed-effects regression. The odds of any severe malaria phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (OR=1.33, 95%CI:1.07-1.64 for a delay of >24 hours vs. ≤24 hours;p=0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children

  • Journal article
    Prah DA, Amoah LE, Gibbins MP, Bediako Y, Cunnington AJ, Awandare GA, Hafalla JCRet al., 2020,

    Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections.

    , Malaria Journal, Vol: 19, Pages: 364-364, ISSN: 1475-2875

    BACKGROUND: The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with acute uncomplicated malaria, despite children being the most vulnerable group. METHODS: Peripheral blood leucocyte subpopulations were characterized in children with acute uncomplicated (symptomatic; n = 25) or asymptomatic (n = 67) P. falciparum malaria, as well as malaria-free (uninfected) children (n = 16) from Obom, a sub-district of Accra, Ghana. Leucocyte subpopulations were enumerated by flow cytometry and correlated with two measures of parasite load: (a) plasma levels of P. falciparum histidine-rich protein 2 (PfHRP2) as a proxy for parasite biomass and (b) peripheral blood parasite densities determined by microscopy. RESULTS: In children with symptomatic P. falciparum infections, the proportions and absolute cell counts of total (CD3 +) T cells, CD4 + T cells, CD8 + T cells, CD19 + B cells and CD11c + dendritic cells (DCs) were significantly lower as compared to asymptomatic P. falciparum-infected and uninfected children. Notably, CD15 + neutrophil proportions and cell counts were significantly increased in symptomatic children. There was no significant difference in the proportions and absolute counts of CD14 + monocytes amongst the three study groups. As expected, measures of parasite load were significantly higher in symptomatic cases. Remarkably, PfHRP2 levels and parasite densities negatively correlated with both the proportions and absolute numbers of peripheral leucocyte subsets: CD3 + T, CD4 + T, CD8 + T, CD19 + B, CD56&th

  • Journal article
    Ashdown G, Gaboriau D, Baum J, 2020,

    A machine learning approach to define antimalarial drug action from heterogeneous cell-based screens

    , Science Advances, Vol: 6, ISSN: 2375-2548

    Drug resistance threatens the effective prevention and treatment of an ever-increasing range ofhuman infections. This highlights an urgent need for new and improved drugs with novelmechanisms of action to avoid cross-resistance. Current cell-based drug screens are,however, restricted to binary live/dead readouts with no provision for mechanism of actionprediction. Machine learning methods are increasingly being used to improve informationextraction from imaging data. Such methods, however, work poorly with heterogeneouscellular phenotypes and generally require time-consuming human-led training. We havedeveloped a semi-supervised machine learning approach, combining human- and machinelabelled training data from mixed human malaria parasite cultures. Designed for highthroughput and high-resolution screening, our semi-supervised approach is robust to naturalparasite morphological heterogeneity and correctly orders parasite developmental stages. Ourapproach also reproducibly detects and clusters drug-induced morphological outliers bymechanism of action, demonstrating the potential power of machine learning for acceleratingcell-based drug discovery.

  • Journal article
    Varghese S, Rahmani R, Drew DR, Beeson JG, Baum J, Smith BJ, Baell Jet al., 2020,

    Structure activity studies of truncated latrunculin analogues with anti-malarial activity

    , ChemMedChem, ISSN: 0014-827X

    Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

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

    Correction: Single-molecule nanopore sensing of actin dynamics and drug binding

    , Chemical Science, Vol: 11, Pages: 8036-8038, ISSN: 2041-6520

    Correction for ‘Single-molecule nanopore sensing of actin dynamics and drug binding’ by Xiaoyi Wang et al., Chem. Sci., 2020, 11, 970–979, DOI: 10.1039/C9SC05710B.

  • 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
    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
    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
    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
    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
    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.

  • 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
    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 KE, Haydn-Smith KL, Sanchez-Roman Teran F, Moura PL, Hawksworth J, Frayne J, Toye AM, Baum Jet al., 2019,

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

    , NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
  • 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
    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 CJet 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.

  • Journal article
    Knuepfer E, Wright KE, Prajapati SK, Rawlinson TA, Mohring F, Koch M, Lyth OR, Howell SA, Villasis E, Snijders AP, Moon RW, Draper SJ, Rosanas-Urgell A, Higgins MK, Baum J, Holder AAet al., 2019,

    Divergent roles for the RH5 complex components, CyRPA and RIPR in human-infective malaria parasites

    , PLOS PATHOGENS, Vol: 15, ISSN: 1553-7366
  • Journal article
    Baragaña B, Forte B, Choi R, Nakazawa Hewitt S, Bueren-Calabuig JA, Pisco JP, Peet C, Dranow DM, Robinson DA, Jansen C, Norcross NR, Vinayak S, Anderson M, Brooks CF, Cooper CA, Damerow S, Delves M, Dowers K, Duffy J, Edwards TE, Hallyburton I, Horst BG, Hulverson MA, Ferguson L, Jiménez-Díaz MB, Jumani RS, Lorimer DD, Love MS, Maher S, Matthews H, McNamara CW, Miller P, O'Neill S, Ojo KK, Osuna-Cabello M, Pinto E, Post J, Riley J, Rottmann M, Sanz LM, Scullion P, Sharma A, Shepherd SM, Shishikura Y, Simeons FRC, Stebbins EE, Stojanovski L, Straschil U, Tamaki FK, Tamjar J, Torrie LS, Vantaux A, Witkowski B, Wittlin S, Yogavel M, Zuccotto F, Angulo-Barturen I, Sinden R, Baum J, Gamo F-J, Mäser P, Kyle DE, Winzeler EA, Myler PJ, Wyatt PG, Floyd D, Matthews D, Sharma A, Striepen B, Huston CD, Gray DW, Fairlamb AH, Pisliakov AV, Walpole C, Read KD, Van Voorhis WC, Gilbert IHet al., 2019,

    Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.

    , Proc Natl Acad Sci U S A

    Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

  • Journal article
    Magombedze G, Ferguson NM, Ghani AC, 2018,

    A trade-off between dry season survival longevity and wet season high net reproduction can explain the persistence of Anopheles mosquitoes.

    , Parasites & Vectors, Vol: 11, ISSN: 1756-3305

    BACKGROUND: Plasmodium falciparum malaria remains a leading cause of death in tropical regions of the world. Despite efforts to reduce transmission, rebounds associated with the persistence of malaria vectors have remained a major impediment to local elimination. One area that remains poorly understood is how Anopheles populations survive long dry seasons to re-emerge following the onset of the rains. METHODS: We developed a suite of mathematical models to explore the impact of different dry-season mosquito survival strategies on the dynamics of vector populations. We fitted these models to an Anopheles population data set from Mali to estimate the model parameters and evaluate whether incorporating aestivation improved the fit of the model to the observed seasonal dynamics. We used the fitted models to explore the impact of intervention strategies that target aestivating mosquitoes in addition to targeting active mosquitoes and larvae. RESULTS: Including aestivation in the model significantly improved our ability to reproduce the observed seasonal dynamics of vector populations as judged by the deviance information criterion (DIC). Furthermore, such a model resulted in more biologically plausible active mosquito survival times (for A. coluzzii median wet season survival time of 10.9 days, 95% credible interval (CrI): 10.0-14.5 days in a model with aestivation versus 38.1 days, 95% CrI: 35.8-42.5 days in a model without aestivation; similar patterns were observed for A. arabiensis). Aestivation also generated enhanced persistence of the vector population over a wider range of both survival times and fecundity levels. Adding vector control interventions that target the aestivating mosquito population is shown to have the potential to enhance the impact of existing vector control. CONCLUSIONS: Dry season survival attributes appear to drive vector population persistence and therefore have implications for vector control. Further research is therefore needed to better u

  • Journal article
    Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, Nolan T, Crisanti Aet al., 2018,

    A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes

    , Nature Biotechnology, Vol: 36, Pages: 1062-1066, ISSN: 1087-0156

    In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive.

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