57 results found
Morang'a CM, Amenga-Etego L, Bah SY, et al., 2020, Machine learning approaches classify clinical malaria outcomes based on haematological parameters, BMC Medicine, Vol: 18, ISSN: 1741-7015
BACKGROUND: Malaria is still a major global health burden, with more than 3.2 billion people in 91 countries remaining at risk of the disease. Accurately distinguishing malaria from other diseases, especially uncomplicated malaria (UM) from non-malarial infections (nMI), remains a challenge. Furthermore, the success of rapid diagnostic tests (RDTs) is threatened by Pfhrp2/3 deletions and decreased sensitivity at low parasitaemia. Analysis of haematological indices can be used to support the identification of possible malaria cases for further diagnosis, especially in travellers returning from endemic areas. As a new application for precision medicine, we aimed to evaluate machine learning (ML) approaches that can accurately classify nMI, UM, and severe malaria (SM) using haematological parameters. METHODS: We obtained haematological data from 2,207 participants collected in Ghana: nMI (n = 978), SM (n = 526), and UM (n = 703). Six different ML approaches were tested, to select the best approach. An artificial neural network (ANN) with three hidden layers was used for multi-classification of UM, SM, and uMI. Binary classifiers were developed to further identify the parameters that can distinguish UM or SM from nMI. Local interpretable model-agnostic explanations (LIME) were used to explain the binary classifiers. RESULTS: The multi-classification model had greater than 85% training and testing accuracy to distinguish clinical malaria from nMI. To distinguish UM from nMI, our approach identified platelet counts, red blood cell (RBC) counts, lymphocyte counts, and percentages as the top classifiers of UM with 0.801 test accuracy (AUC = 0.866 and F1 score = 0.747). To distinguish SM from nMI, the classifier had a test accuracy of 0.96 (AUC = 0.983 and F1 score = 0.944) with mean platelet volume and mean cell volume being the unique classifiers of SM. Random forest was used
Thompson H, Hogan A, Walker P, et 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.
Mousa A, Al-Taiar A, Anstey NM, et 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
Prah DA, Amoah LE, Gibbins MP, et 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
Montaldo P, Cunnington A, Oliveira V, et al., 2020, Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy, Scientific Reports, Vol: 10, Pages: 1-7, ISSN: 2045-2322
A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection.
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.
Ebmeier S, Cunnington AJ, 2020, Correspondence regarding recently published editorial: ‘Will children reveal their secret? The coronavirus dilemma’, European Respiratory Journal, Vol: 56, Pages: 1-3, ISSN: 0903-1936
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.
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.
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
Knackstedt S, Georgiadou A, Apel F, et al., 2019, Neutrophil extracellular traps drive inflammatory pathogenesis in malaria, Science Immunology, Vol: 4, Pages: 1-17, ISSN: 2470-9468
Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs). This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via GCSF production, and induction of the endothelial cytoadhesion receptor ICAM-1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.
Levin M, Cunnington AJ, Hoggart CJ, 2019, Secondary re-analysis of the FEAST trial - Authors' reply, The Lancet Respiratory Medicine, Vol: 7, Pages: e31-e31, ISSN: 2213-2600
Charani E, Cunnington AJ, Yousif AHA, et 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.
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
Evans C, Fitzgerald F, Cunnington A, 2019, Review of UK malaria treatment guidelines 2016, Archives of Disease in Childhood.education and Practice Edition, Vol: 104, Pages: 218-220, ISSN: 1743-0585
Levin M, Cunnington A, Hoggart C, 2019, Adverse effects of saline or albumin fluid bolus in resuscitation: response to Maitland et al. and Quartagno et al., Lancet Respiratory Medicine, ISSN: 2213-2600
Levin M, Cunnington AJ, Wilson C, et 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
Georgiadou A, Lee HJ, Walther M, et 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.
Georgiadou A, Barrio PS, Dunican C, et al., 2019, COMPARATIVE TRANSCRIPTOMICS IDENTIFIES PHENOTYPIC SIMILARITIES BETWEEN MOUSE MODELS AND HUMAN SEVERE MALARIA, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 8-8, ISSN: 0002-9637
Mousa A, Challenger JD, Cunnington AJ, et al., 2019, THE EFFECT OF DELAYED TREATMENT ON PROGRESSION TO SEVERE PLASMODIUM FALCIPARUM MALARIA: A POOLED MULTICENTRE INDIVIDUAL-PATIENT ANALYSIS, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 215-215, ISSN: 0002-9637
van Beek A, Pouw R, Sarr I, et al., 2018, Complement factor H levels associate with severity of Plasmodium falciparum malaria, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 234-234, ISSN: 0161-5890
van Beek AE, Sarr I, Correa S, et al., 2018, Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity., Open Forum Infect Dis, Vol: 5, ISSN: 2328-8957
Background: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity. Methods: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity. Results: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load. Conclusions: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.
Lee HJ, Georgiadou A, Walther M, et al., 2018, Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria, Science Translational Medicine, Vol: 10, ISSN: 1946-6234
The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule-related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.
Mcardle A, Turkova A, Cunnington A, 2018, When do co-infections matter?, Current Opinion in Infectious Diseases, Vol: 31, Pages: 209-215, ISSN: 0951-7375
Purpose of review: Advances in diagnostic methods mean that co-infections are increasingly being detected in clinical practice, yet their significance is not always obvious. In parallel, basic science studies are increasingly investigating interactions between pathogens to try to explain real-life observations and elucidate biological mechanisms. Recent findings: Co-infections may be insignificant, detrimental or even beneficial, and these outcomes can occur through multiple levels of interactions which include modulation of the host response, altering the performance of diagnostic tests and drug-drug interactions during treatment. The harmful effects of chronic co-infections such as tuberculosis or Hepatitis B and C in association with HIV are well established, and recent studies have focussed on strategies to mitigate these effects. However consequences of many acute co-infections are much less certain, and recent conflicting findings simply highlight many of the challenges of studying naturally acquired infections in humans. Summary: Tackling these challenges, using animal models or careful prospective studies in humans may prove to be worthwhile. There are already tantalising examples where identification and treatment of relevant co-infections seems to hold promise for improved health outcomes.
Lee HJ, Georgiadou A, Otto T, et al., 2018, Transcriptomic studies in malaria – a paradigm for investigation of systemic host-pathogen interactions, Microbiology and Molecular Biology Reviews, Vol: 82, ISSN: 1092-2172
Transcriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analysis of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions. This exciting prospect is not without challenges, especially as focus moves from interactions in vitro under tightly controlled conditions to tissue-and systemic-level interactions in animal models and natural and experimental infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria, a parasitic disease which has exerted a major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria as a paradigm for transcriptomic assessment of systemic host-pathogen interaction in humans, because much of the direct host-pathogen interaction occurs within the blood–a readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria, and how these may guide studies of host-pathogen interaction in other infectious diseases. We propose that the potential of transcriptomic studies to improve understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence of technological constraints. Further advances will require integration of transcriptomic data with analytical approaches from other scientific disciplines including epidemiology and mathematical modelling.
Georgiadou A, Bretscher M, Lee H, et al., 2018, COMBINING RNA-SEQUENCING AND MATHEMATICAL MODELLING TO IDENTIFY MECHANISTIC CORRELATES OF PROTECTION IN MALARIA, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 27-27, ISSN: 0002-9637
Ikeda AK, Rowley C, Yang Y, et al., 2017, PLASMA HAPTOGLOBIN AS A MARKER OF CLINICAL SEVERITY IN GAMBIAN AND MALAWIAN CHILDREN INFECTED WITH PLASMODIUM FALCIPARUM, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 464-464, ISSN: 0002-9637
Lee HJ, Walther M, Georgiadou A, et al., 2017, Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>The pathogenesis of severe <jats:italic>Plasmodium falciparum</jats:italic> malaria is incompletely understood. Since the pathogenic stage of the parasite is restricted to blood, dual RNA-sequencing of host and parasite transcripts in blood can reveal their interactions at a systemic scale. Here we identify human and parasite gene expression associated with severe disease features in Gambian children. Differences in parasite load explained up to 99% of differential expression of human genes but only a third of the differential expression of parasite genes. Co-expression analyses showed a remarkable co-regulation of host and parasite genes controlling translation, and host granulopoiesis genes uniquely co-regulated and differentially expressed in severe malaria. Our results indicate that high parasite load is the proximal stimulus for severe <jats:italic>P. falciparum</jats:italic> malaria, that there is an unappreciated role for many parasite genes in determining virulence, and hint at a molecular arms-race between host and parasite to synthesise protein products.</jats:p>
Soothill G, Darboe S, Bah G, et al., 2017, Invasive bacterial infections in gambian patients with Sickle Cell Anemia in an era of widespread pneumococcal and haemophilus influenza type B vaccination, 22nd Congress of the European-Hematology-Association, Publisher: Ferrata Storti Foundation, Pages: 606-606, ISSN: 0390-6078
Cheung R, Cunnington A, Drysdale S, et al., 2017, 100 Cases in Paediatrics, Second Edition, Publisher: CRC Press, ISBN: 9781315351599
The new edition of this best-selling title from the popular 100 cases series explores common paediatric scenarios that will be encountered by the medical student and junior doctor during practical training on the ward, in the emergency ...
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