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      Killer Bee Molecules: Antimicrobial Peptides as Effector Molecules to Target Sporogonic Stages of Plasmodium

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms.

          Author Summary

          Breaking the complex life cycle of malaria by blocking its development in the mosquito is one area of research being pursued for malaria control. Currently, the mosquito itself, or microbes that live within it, are being genetically modified to provide toxic or lethal outcomes to the parasite. However, this usually comes with a cost to the lifespan and reproductive capabilities of the mosquito, resulting in a strong disadvantage if these modified organisms were to be released in the wild. This work aimed to identify a group of molecules suitable for inclusion in genetic modification strategies, which are toxic to malaria parasites, but have no costly side-effects to the mosquito. Within this group of molecules, toxins from bee and wasp venoms were prominent in their effects on mouse and human parasites. These particular molecules may prove effective in novel malaria control strategies and such venoms may also be a promising source of additional anti-malaria toxins.

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          Most cited references 88

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          Natural microbe-mediated refractoriness to Plasmodium infection in Anopheles gambiae.

          Malaria parasite transmission depends on the successful transition of Plasmodium through discrete developmental stages in the lumen of the mosquito midgut. Like the human intestinal tract, the mosquito midgut contains a diverse microbial flora, which may compromise the ability of Plasmodium to establish infection. We have identified an Enterobacter bacterium isolated from wild mosquito populations in Zambia that renders the mosquito resistant to infection with the human malaria parasite Plasmodium falciparum by interfering with parasite development before invasion of the midgut epithelium. Phenotypic analyses showed that the anti-Plasmodium mechanism requires small populations of replicating bacteria and is mediated through a mosquito-independent interaction with the malaria parasite. We show that this anti-Plasmodium effect is largely caused by bacterial generation of reactive oxygen species.
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            Simultaneous identification of species and molecular forms of the Anopheles gambiae complex by PCR-RFLP.

            For differential identification of sibling species in the Anopheles gambiae Giles complex (Diptera: Culicidae), including simultaneous separation of M and S molecular forms within An. gambiae Giles sensu stricto, we describe a PCR-RFLP method. This procedure is more efficient, faster and cheaper than those used before, so is recommended for large-scale processing of field-collected larval and adult specimens to be identified in malaria vector studies.
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              Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study.

              Substantial reductions in malaria have been reported in several African countries after distribution of insecticide-treated bednets and the use of artemisinin-based combination therapies (ACTs). Our aim was to assess the effect of these policies on malaria morbidity, mosquito populations, and asymptomatic infections in a west African rural population. We did a longitudinal study of inhabitants of Dielmo village, Senegal, between January, 2007, and December, 2010. We monitored the inhabitants for fever during this period and we treated malaria attacks with artesunate plus amodiaquine. In July, 2008, we offered longlasting insecticide (deltamethrin)-treated nets (LLINs) to all villagers. We did monthly night collections of mosquitoes during the whole study period, and we assessed asymptomatic carriage from cross-sectional surveys. Our statistical analyses were by negative binomial regression, logistic regression, and binomial or Fisher exact test. There were 464 clinical malaria attacks attributable to Plasmodium falciparum during 17,858 person-months of follow-up. The incidence density of malaria attacks averaged 5·45 (95% CI 4·90-6·05) per 100 person-months between January, 2007, and July, 2008, before the distribution of LLINs. Incidence density decreased to 0·41 (0·29-0·55) between August, 2008, and August, 2010, but increased back to 4·57 (3·54-5·82) between September and December, 2010--ie, 27-30 months after the distribution of LLINs. The rebound of malaria attacks were highest in adults and children aged 10 years or older: 45 (63%) of 71 malaria attacks recorded in 2010 compared with 126 (33%) of 384 in 2007 and 2008 (p<0·0001). 37% of Anopheles gambiae mosquitoes were resistant to deltamethrin in 2010, and the prevalence of the Leu1014Phe kdr resistance mutation increased from 8% in 2007 to 48% in 2010 (p=0·0009). Increasing pyrethroid resistance of A gambiae and increasing susceptibility of older children and adults, probably due to decreasing immunity, caused the rebound and age shift of malaria morbidity. Strategies to address the problem of insecticide resistance and to mitigate its effects must be urgently defined and implemented. Institut de Recherche pour le Développement and the Pasteur Institute of Dakar. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                November 2013
                November 2013
                21 November 2013
                : 9
                : 11
                Affiliations
                [1 ]Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele, Staffordshire, United Kingdom
                [2 ]Malaria Research and Training Centre (MRTC), Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali
                [3 ]Centre National de Transfusion Sanguine, Bamako, Mali
                [4 ]Institut Pasteur, Centre for Production and Infection of Anopheles (CEPIA), Parasitology and Mycology Department, Paris, France
                [5 ]Department of Neurochemistry Svante Arrhenius v. 21A, Stockholm University, Stockholm, Sweden
                [6 ]Department of Molecular Bioscience, the Wenner-Gren Institute, Svante Arrhenius v. 20C, Stockholm University, Stockholm, Sweden
                [7 ]Temple University Department of Biology, Philadelphia, Pennsylvania, United States of America
                [8 ]Howard Florey Research Laboratories, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
                Stanford University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HH VC MBC SFT FT PE. Performed the experiments: VC AU HH ILT CB AZ IB LS. Analyzed the data: VC. Contributed reagents/materials/analysis tools: CB UL IF LO JDW MB. Wrote the paper: VC HH. Reviewed/commented on the manuscript: VC HH PE LO CB.

                Article
                PPATHOGENS-D-13-01451
                10.1371/journal.ppat.1003790
                3836994

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                Funding
                This work was supported by Wellcome Trust Programme Grant 084582, awarded to PE, HH, and FT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Infectious disease & Microbiology

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