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Slack R.D.,Johns Hopkins University | Jacobine A.M.,Johns Hopkins University | Posner G.H.,Johns Hopkins University | Posner G.H.,Johns Hopkins Malaria Research Institute
MedChemComm | Year: 2012

Cyclic peroxides such as the plant-derived 1,2,4-trioxane artemisinin and its derivatives are short-lived, rapidly-acting antimalarials that are now usually combined with standard long-lived, alkaloidal antimalarials; such artemisinin combination therapy (ACT) is the worldwide standard operating procedure for malaria chemotherapy. This review discusses antimalarial monomeric and dimeric derivatives of artemisinin, peroxides not derived from artemisinin, and finally hybrids containing one peroxide unit covalently linked to a non-peroxide unit. Emphasis is placed on the antimalarial effectiveness of these diverse cyclic peroxides and on the simplicity of their synthesis. © 2012 The Royal Society of Chemistry.

Venkatesan M.,Johns Hopkins University | Venkatesan M.,Howard Hughes Medical Institute | Rasgon J.L.,Johns Hopkins University | Rasgon J.L.,Johns Hopkins Malaria Research Institute
Molecular Ecology | Year: 2010

After introduction, West Nile virus (WNV) spread rapidly across the western United States between the years 2001 and 2004. This westward movement is thought to have been mediated by random dispersive movements of resident birds. Little attention has been placed on the role of mosquito vectors in virus dispersal across North America. The mosquito vector largely responsible for WNV amplification and transmission of WNV in the western USA is Culex tarsalis. Here we present population genetic data that suggest a potential role for C. tarsalis in the dispersal of WNV across the western USA. Population genetic structure across the species range of C. tarsalis in the USA was characterized in 16 states using 12 microsatellite loci. structure and geneland analyses indicated the presence of three broad population clusters. Barriers to gene flow were resolved near the Sonoran desert in southern Arizona and between the eastern Rocky Mountains and High Plains plateau. Small genetic distances among populations within clusters indicated that gene flow was not obstructed over large portions of the West Coast and within the Great Plains region. Overall, gene flow in C. tarsalis appears to be extensive, potentially mediated by movement of mosquitoes among neighbouring populations and hindered in geographically limited parts of its range. The pattern of genetic clustering in C. tarsalis is congruent with the pattern of invasion of WNV across the western United States, raising the possibility that movement of this important vector may be involved in viral dispersal. © 2010 Blackwell Publishing Ltd.

Cohen J.M.,Clinton Health Access Initiative | Smith D.L.,Johns Hopkins Malaria Research Institute | Smith D.L.,Center for Disease Dynamics | Cotter C.,University of California at San Francisco | And 4 more authors.
Malaria Journal | Year: 2012

Background: Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. Methods: A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. Results: The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%). Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance. Conclusions: Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining todays successful malaria control programmes. © 2012 Cohen et al.; licensee BioMed Central Ltd.

Douglas R.G.,University of Heidelberg | Amino R.,Institute Pasteur Paris | Sinnis P.,Johns Hopkins Malaria Research Institute | Frischknecht F.,University of Heidelberg
Trends in Parasitology | Year: 2015

Malaria parasites undergo a complex life cycle between their hosts and vectors. During this cycle the parasites invade different types of cells, migrate across barriers, and transfer from one host to another. Recent literature hints at a misunderstanding of the difference between active, parasite-driven migration and passive, circulation-driven movement of the parasite or parasite-infected cells in the various bodily fluids of mosquito and mammalian hosts. Because both active migration and passive transport could be targeted in different ways to interfere with the parasite, a distinction between the two ways the parasite uses to get from one location to another is essential. We discuss the two types of motion needed for parasite dissemination and elaborate on how they could be targeted by future vaccines or drugs. © 2015 Elsevier Ltd.

Rasgon J.L.,Johns Hopkins Malaria Research Institute
Future microbiology | Year: 2011

EVALUATION OF: Fang W, Vega-Rodríguez J, Ghosh AK et al. Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science 331(6020), 1074-1077 (2011). Paratransgenesis is the genetic manipulation of insect endosymbiotic microorganisms such as bacteria, viruses or fungi. Paratransgenesis has been proposed as a potential method to control vector-borne diseases such as malaria. In this article, Fang and colleagues have used genetic manipulation to insert multiple antimalaria effector genes into the entomopathogenic fungus Metarhizium anisopliae. When the modified fungus was used to infect Anopheles mosquitoes, it expressed the antimalaria effector molecules in the mosquito hemolymph. When several different effector molecules were coexpressed, malaria levels in the mosquito salivary glands were inhibited by up to 98% compared with controls. Significant inhibition could be initiated by as little as seven fungal spores and was very rapid and long lasting. These data suggest that recombinant entomopathogenic fungi could be deployed as part of a strategy to control malaria.

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