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      Engineered Resistance to Plasmodium falciparum Development in Transgenic Anopheles stephensi

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          Abstract

          Transposon-mediated transformation was used to produce Anopheles stephensi that express single-chain antibodies (scFvs) designed to target the human malaria parasite, Plasmodium falciparum. The scFvs, m1C3, m4B7, and m2A10, are derived from mouse monoclonal antibodies that inhibit either ookinete invasion of the midgut or sporozoite invasion of salivary glands. The scFvs that target the parasite surface, m4B7 and m2A10, were fused to an Anopheles gambiae antimicrobial peptide, Cecropin A. Previously-characterized Anopheles cis-acting DNA regulatory elements were included in the transgenes to coordinate scFv production with parasite development. Gene amplification and immunoblot analyses showed promoter-specific increases in transgene expression in blood-fed females. Transgenic mosquito lines expressing each of the scFv genes had significantly lower infection levels than controls when challenged with P. falciparum .

          Author Summary

          Malaria eradication will require vector-control strategies that are both self-sustaining and not affected by migration of infected humans and mosquitoes. Replacement of wild malaria-susceptible mosquito populations with transgenic strains refractory to parasite development could interrupt the cycle of disease transmission and support eradication efforts. Production of P. falciparum -resistant mosquitoes is a necessary first step towards investigating the population replacement strategy. Here we show that An. stephensi engineered to produce P. falciparum -targeting effector molecules are resistant to this important human malaria parasite. Two of the three effector molecules represent a novel combination of components derived from the immune systems of mosquitoes and mice. An important feature of these molecules is that they are unlikely to significantly harm the mosquito, as the mosquito component is an Anopheles antimicrobial peptide with activity against Plasmodium, while the other component is based on a murine antibody selected for its ability to bind specifically to a parasite protein. Transgenes with this design coupled with a gene-drive system could be used alongside vaccines and drugs to provide sustainable local elimination of malaria as part of a long-term strategy for eradication.

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          Most cited references 43

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          The global distribution of clinical episodes of Plasmodium falciparum malaria.

          Interest in mapping the global distribution of malaria is motivated by a need to define populations at risk for appropriate resource allocation and to provide a robust framework for evaluating its global economic impact. Comparison of older and more recent malaria maps shows how the disease has been geographically restricted, but it remains entrenched in poor areas of the world with climates suitable for transmission. Here we provide an empirical approach to estimating the number of clinical events caused by Plasmodium falciparum worldwide, by using a combination of epidemiological, geographical and demographic data. We estimate that there were 515 (range 300-660) million episodes of clinical P. falciparum malaria in 2002. These global estimates are up to 50% higher than those reported by the World Health Organization (WHO) and 200% higher for areas outside Africa, reflecting the WHO's reliance upon passive national reporting for these countries. Without an informed understanding of the cartography of malaria risk, the global extent of clinical disease caused by P. falciparum will continue to be underestimated.
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            Codon usage tabulated from international DNA sequence databases: status for the year 2000.

             Y. Nakamura (2000)
            The frequencies of each of the 257 468 complete protein coding sequences (CDSs) have been compiled from the taxonomical divisions of the GenBank DNA sequence database. The sum of the codons used by 8792 organisms has also been calculated. The data files can be obtained from the anonymous ftp sites of DDBJ, Kazusa and EBI. A list of the codon usage of genes and the sum of the codons used by each organism can be obtained through the web site http://www.kazusa.or.jp/codon/. The present study also reports recent developments on the WWW site. The new web interface provides data in the CodonFrequency-compatible format as well as in the traditional table format. The use of the database is facilitated by keyword based search analysis and the availability of codon usage tables for selected genes from each species. These new tools will provide users with the ability to further analyze for variations in codon usage among different genomes.
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              Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite.

              Malaria is estimated to cause 0.7 to 2.7 million deaths per year, but the actual figures could be substantially higher owing to under-reporting and difficulties in diagnosis. If no new control measures are developed, the malaria death toll is projected to double in the next 20 years. Efforts to control the disease are hampered by drug resistance in the Plasmodium parasites, insecticide resistance in mosquitoes, and the lack of an effective vaccine. Because mosquitoes are obligatory vectors for malaria transmission, the spread of malaria could be curtailed by rendering them incapable of transmitting parasites. Many of the tools required for the genetic manipulation of mosquito competence for malaria transmission have been developed. Foreign genes can now be introduced into the germ line of both culicine and anopheline mosquitoes, and these transgenes can be expressed in a tissue-specific manner. Here we report on the use of such tools to generate transgenic mosquitoes that express antiparasitic genes in their midgut epithelium, thus rendering them inefficient vectors for the disease. These findings have significant implications for the development of new strategies for malaria control.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                April 2011
                April 2011
                21 April 2011
                : 7
                : 4
                Affiliations
                [1 ]Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, California, United States of America
                [2 ]Division of Infectious Diseases, Department of Medicine, University of California-San Diego School of Medicine, La Jolla, California, United States of America
                [3 ]Department of Molecular Biology and Biochemistry, University of California, Irvine, California, United States of America
                [4 ]Department of Parasitology, School of Public Health and Tropical Medicine, Southern Medical University, Guang Zhou, GD, China
                [5 ]Department of Entomology and Nematology, University of Florida, Gainesville, Florida, United States of America
                [6 ]USDA/ARS, Center for Medical, Agricultural and Veterinary Entomology, Gainesville, Florida, United States of America
                University of Notre Dame, United States of America
                Author notes

                Conceived and designed the experiments: ATI FL NJ XC XN OM JMV AAJ. Performed the experiments: ATI FL NJ. Analyzed the data: ATI FL NJ XC XN OM JMV AAJ. Wrote the paper: ATI FL OM JMV AAJ.

                Article
                PPATHOGENS-D-10-00014
                10.1371/journal.ppat.1002017
                3080844
                21533066
                Isaacs et al. 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
                Categories
                Research Article
                Biology
                Biotechnology
                Genetic Engineering
                Transgenics
                Genetics
                Molecular Genetics
                Gene Regulation
                Medicine
                Infectious Diseases
                Parasitic Diseases
                Malaria

                Infectious disease & Microbiology

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