The evolution of drug-resistant malaria

Howard Hughes Medical Institute, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Transactions of the Royal Society of Tropical Medicine and Hygiene (Impact Factor: 1.84). 04/2009; 103 Suppl 1(1):S11-4. DOI: 10.1016/j.trstmh.2008.11.002
Source: PubMed


Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted from a talk given in honour of Professor Malcolm Molyneux in Liverpool in September 2008, reviews the rise and fall of clinically important forms of drug-resistant falciparum malaria and considers how lessons learned from studying the evolution of drug-resistant malaria can be applied to efforts to prevent and deter resistance.

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Available from: Christopher V Plowe
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    • ", when artemisinin efficacy is compromised, the partner drugs in the ACT are then under very strong selection [13]. Drug resistant parasites have emerged and spread even when effective drugs have been deployed [14] [15]. Moreover, insecticide resistant mosquito vectors have emerged and continued to transmit malaria after the introduction of insecticides [16] [15]. "
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    • "which affects millions of people around the world, predominantly in developing countries (WHO, 2014). No effective vaccines against malaria have yet been licensed and both the vector (mosquito) and the parasite are becoming increasingly resistant against chemical control measures as well as prophylactic and therapeutic agents, thus presenting a major global health problem (Fairhurst et al., 2012; Plowe, 2009). The life cycle of Plasmodium falciparum provides three targets for vaccine development: (i) The pre-erythrocytic stage (start of the infection, no clinical symptoms); (ii) the erythrocytic stage (asexual reproduction of the parasite in the blood stream and manifestation of clinical symptoms); and (iii) the sexual stage (uptake of sexual forms of the parasite by mosquitoes and transmission to new individuals). "
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    ABSTRACT: Malaria is a vector-borne disease affecting more than two million people and accounting for more than 600,000 deaths each year, especially in developing countries. The most serious form of malaria is caused by Plasmodium falciparum. The complex life cycle of this parasite, involving pre-erythrocytic, asexual and sexual stages, makes vaccine development cumbersome but also offers a broad spectrum of vaccine candidates targeting exactly those stages. Vaccines targeting the sexual stage of P. falciparum are called transmission-blocking vaccines (TBVs). They do not confer protection for the vaccinated individual but aim to reduce or prevent the transmission of the parasite within a population and are therefore regarded as an essential tool in the fight against the disease. Malaria predominantly affects large populations in developing countries, so TBVs need to be produced in large quantities at low cost. Combining the advantages of eukaryotic expression with a virtually unlimited upscaling potential and a good product safety profile, plant-based expression systems represent a suitable alternative for the production of TBVs. We report here the high level (300 µg per g fresh leaf weight (FLW)) transient expression in Nicotiana benthamiana leaves of an effective TBV candidate based on a fusion protein F0 comprising Pfs25 and the C0-domain of Pfs230, and the implementation of a simple and cost-effective heat treatment step for purification that yields intact recombinant protein at >90% purity with a recovery rate of >70%. The immunization of mice clearly showed that antibodies raised against plant-derived F0 completely blocked the formation of oocysts in a malaria transmission-blocking assay (TBA) making F0 an interesting TBV candidate or a component of a multi-stage malaria vaccine cocktail. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • "Drug pressure in the field is also considered to be an essential prerequisite for the development of resistance (Wellems 2002, Plowe 2009). However, the rate at which drug resistance spreads and how the resistant mutants survive in nature are still a matter of investigation (Talisuna et al. 2004, Anderson & Roper 2005, Hyde 2005). Several models, including the degree of drug use, drug elimination half-life, host heterogeneity (Hastings et al. 2002), parasite biomass (Hastings & D'Alessandro 2000), parasite fitness (Walliker et al. 2005), malaria transmission intensity (Hastings & Watkins 2005), host immunity and intrahost dynamics (Hastings 1997), were developed to better understand this drug resistance (Talisuna et al. 2003, 2004, 2007). "
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