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Journal articleDembele L, Franetich J-F, Lorthiois A, et al., 2014,
Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures
, Nature Medicine, Vol: 20, Pages: 307-312, ISSN: 1078-8956Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi–infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.
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Journal articleGriffin JT, Ferguson NM, Ghani AC, 2014,
Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa
, Nature Communications, Vol: 5, ISSN: 2041-1723Estimating the changing burden of malaria disease remains difficult owing to limitations inhealth reporting systems. Here, we use a transmission model incorporating acquisition andloss of immunity to capture age-specific patterns of disease at different transmissionintensities. The model is fitted to age-stratified data from 23 sites in Africa, and we thenproduce maps and estimates of disease burden. We estimate that in 2010 there were 252(95% credible interval: 171–353) million cases of malaria in sub-Saharan Africa that activecase finding would detect. However, only 34% (12–86%) of these cases would be observedthrough passive case detection. We estimate that the proportion of all cases of clinicalmalaria that are in under-fives varies from above 60% at high transmission to below 20% atlow transmission. The focus of some interventions towards young children may need to bereconsidered, and should be informed by the current local transmission intensity.
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Journal articleCunnington AJ, Riley EM, Walther M, 2013,
Stuck in a rut? Reconsidering the role of parasite sequestration in severe malaria syndromes
, TRENDS IN PARASITOLOGY, Vol: 29, Pages: 585-592, ISSN: 1471-4922- Author Web Link
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- Citations: 49
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Journal articleCunnington AJ, Walther M, Riley EM, 2013,
Piecing Together the Puzzle of Severe Malaria
, SCIENCE TRANSLATIONAL MEDICINE, Vol: 5, ISSN: 1946-6234 -
Journal articleMarshall JM, White MT, Ghani AC, et al., 2013,
Quantifying the mosquito's sweet tooth: modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control
, Malaria Journal, Vol: 12, ISSN: 1475-2875Background: Current vector control strategies focus largely on indoor measures, such as long-lasting insecticidetreated nets (LLINs) and indoor residual spraying (IRS); however mosquitoes frequently feed on sugar sourcesoutdoors, inviting the possibility of novel control strategies. Attractive toxic sugar baits (ATSB), either sprayed onvegetation or provided in outdoor bait stations, have been shown to significantly reduce mosquito densities inthese settings.Methods: Simple models of mosquito sugar-feeding behaviour were fitted to data from an ATSB field trial in Maliand used to estimate sugar-feeding rates and the potential of ATSB to control mosquito populations. The modeland fitted parameters were then incorporated into a larger integrated vector management (IVM) model to assessthe potential contribution of ATSB to future IVM programmes.Results: In the Mali experimental setting, the model suggests that about half of female mosquitoes fed on ATSBsolution per day, dying within several hours of ingesting the toxin. Using a model incorporating the number ofgonotrophic cycles completed by female mosquitoes, a higher sugar-feeding rate was estimated for youngermosquitoes than for older mosquitoes. Extending this model to incorporate other vector control interventionssuggests that an IVM programme based on both ATSB and LLINs may substantially reduce mosquito density andsurvival rates in this setting, thereby substantially reducing parasite transmission. This is predicted to exceed theimpact of LLINs in combination with IRS provided ATSB feeding rates are 50% or more of Mali experimental levels.In addition, ATSB is predicted to be particularly effective against Anopheles arabiensis, which is relatively exophilicand therefore less affected by IRS and LLINs.Conclusions: These results suggest that high coverage with a combination of LLINs and ATSB could result insubstantial reductions in malaria transmission in this setting. Further field studies of ATSB in other settings
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Journal articleWhite MT, Griffin JT, Ghani AC, 2013,
The design and statistical power of treatment re-infection studies of the association between pre-erythrocytic immunity and infection with Plasmodium falciparum
, Malaria Journal, Vol: 12, ISSN: 1475-2875Background: Understanding the role of pre-erythrocytic immune responses to Plasmodium falciparum parasites iscrucial for understanding the epidemiology of malaria. However, published studies have reported inconsistentresults on the association between markers of pre-erythrocytic immunity and protection from malaria.Methods: The design and statistical methods of studies of pre-erythrocytic immunity were reviewed, and factorsaffecting the likelihood of detecting statistically significant associations were assessed. Treatment re-infectionstudies were simulated to estimate the effects of study size, transmission intensity, and sampling frequency on thestatistical power to detect an association between markers of pre-erythrocytic immunity and protection frominfection.Results: Nine of nineteen studies reviewed reported statistically significant associations between markers ofpre-erythrocytic immunity and protection from infection. Studies with large numbers of participants inhigh-transmission settings, followed longitudinally with active detection of infection and with immune responsesanalysed as continuous variables, were most likely to detect statistically significant associations. Simulation oftreatment re-infection studies highlights that many studies are underpowered to detect statistically significantassociations, providing an explanation for the finding that only some studies report significant associations betweenpre-erythrocytic immune responses and protection from infection.Conclusions: The findings of the review and model simulations are consistent with the hypothesis thatpre-erythrocytic immune responses prevent P. falciparum infections, but that many studies are underpowered toconsistently detect this effect.
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Journal articleBlagborough AM, Churcher TS, Upton LM, et al., 2013,
Transmission-blocking interventions eliminate malaria from laboratory populations
, Nature Communications, Vol: 4, ISSN: 2041-1723Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field.
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Journal articleBejon P, White MT, Olotu A, et al., 2013,
Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data
, LANCET INFECTIOUS DISEASES, Vol: 13, Pages: 319-327, ISSN: 1473-3099- Author Web Link
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- Citations: 68
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Journal articleRao VB, Schellenberg D, Ghani AC, 2013,
Overcoming health systems barriers to successful malaria treatment
, TRENDS IN PARASITOLOGY, Vol: 29, Pages: 164-180, ISSN: 1471-4922- Author Web Link
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- Citations: 52
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Journal articleWalker PGT, Griffin JT, Cairns M, et al., 2013,
A model of parity-dependent immunity to placental malaria
, Nature Communications, Vol: 4, ISSN: 2041-1723Plasmodium falciparum placental infection during pregnancy is harmful for both mother andchild. Protection from placental infection is parity-dependent, that is, acquired over consecutivepregnancies. However, the infection status of the placenta can only be assessed atdelivery. Here, to better understand the mechanism underlying this parity-dependence, wefitted a model linking malaria dynamics within the general population to observed placentalhistology. Our results suggest that immunity resulting in less prolonged infection is a greaterdeterminant of the parity-specific patterns than immunity that prevents placental sequestration.Our results also suggest the time when maternal blood first flows into the placenta isa high-risk period. Therefore, preventative strategies implementable before or early inpregnancy, such as insecticide-treated net usage in women of child-bearing age or any futurevaccine, could substantially reduce the number of women who experience placental infection.
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Journal articleCunnington AJ, Bretscher MT, Nogaro SI, et al., 2013,
Comparison of parasite sequestration in uncomplicated and severe childhood Plasmodium falciparum malaria
, Journal of Infection -
Journal articleMalmquist NA, Moss TA, Mecheri S, et al., 2012,
Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in <i>Plasmodium falciparum</i>
, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 16708-16713, ISSN: 0027-8424- Author Web Link
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- Citations: 101
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.
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