Mass Production of Genetically Modified <em>Aedes aegypti</em> for Field Releases in Brazil

New techniques and methods are being sought to try to win the battle against mosquitoes. Recent advances in molecular techniques have led to the ...

Oxitec Ltd

Suppression or elimination of vector populations is a tried and tested method for reducing vector-borne disease, and a key component of integrated control programs. Genetic methods have the potential to provide new and improved methods for vector control. The required genetic technology is simpler than that required for strategies based on population replacement and is likely to be available earlier. In particular, genetic methods that enhance the Sterile Insect Technique (e.g., RIDL) are already available for some species.

Insect population suppression using engineered insects.

Dengue e la febbre emorragica dengue sono in aumento i problemi di salute pubblica con un stimato 50 milioni di nuove infezioni ogni anno. Aedes aegypti &egrave; che il vettore principale del virus dengue nella sua gamma e il controllo di questa zanzara ridurrebbe la mortalit&agrave; e la morbilit&agrave; significativamente umana. Metodi di controllo presenti zanzare non sono sufficientemente efficaci e nuovi approcci sono necessari urgentemente. Una strategia di &quot;sterile-maschio-release&quot; basata sul rilascio di zanzare che trasportano un gene letale dominante condizionale &egrave; una nuova metodologia di controllo attraente. Ceppi transgenici di Aedes aegypti sono stati progettati per avere un reprensibile fenotipo flightless femmina-specifici utilizzando due transgeni separati o un transgene unico, basato sull&#39;uso di un promotore muscolare indiretto volo femmina-specifici dal gene Aedes aegypti actina-4. Questi ceppi eliminano la necessit&agrave; di sterilizzazione per irraggiamento, permettono il rilascio esclusivamente maschile (&quot;sessaggio genetico&quot;) e consentono il rilascio delle uova invece di adulti. Inoltre, questi ceppi sono attesi per facilitare il controllo di tutta l&#39;area o l&#39;eliminazione di dengue se adottato come parte di una strategia di gestione integrata dei parassiti.

Fenotipo flightless femmina-specifici per il controllo della zanzara.

&#x767B;&#x9769;&#x70ED;&#x548C;&#x767B;&#x9769;&#x51FA;&#x8840;&#x70ED;&#x6BCF;&#x5E74;&#x589E;&#x52A0;&#x4F30;&#x8BA1;&#x7684; 5000 &#x4E07;&#x65B0;&#x611F;&#x67D3;&#x7684;&#x516C;&#x5171;&#x536B;&#x751F;&#x95EE;&#x9898;&#x3002;&#x57C3;&#x53CA;&#x4F0A;&#x868A;&#x662F;&#x5728;&#x5176;&#x8303;&#x56F4;&#x5185;&#x7684;&#x767B;&#x9769;&#x70ED;&#x75C5;&#x6BD2;&#x7684;&#x4E3B;&#x8981;&#x8F7D;&#x4F53;&#x548C;&#x63A7;&#x5236;&#x8FD9;&#x868A;&#x5B50;&#x4F1A;&#x964D;&#x4F4E;&#x5927;&#x5927;&#x4EBA;&#x7C7B;&#x53D1;&#x75C5;&#x7387;&#x548C;&#x6B7B;&#x4EA1;&#x7387;&#x3002;&#x76EE;&#x524D;&#x7684;&#x868A;&#x5B50;&#x63A7;&#x5236;&#x65B9;&#x6CD5;&#x8FD8;&#x4E0D;&#x591F;&#x6709;&#x6548;&#xFF0C;&#x8FEB;&#x5207;&#x9700;&#x8981;&#x65B0;&#x7684;&#x529E;&#x6CD5;&#x3002;&#x57FA;&#x4E8E;&#x5E26;&#x6709;&#x6761;&#x4EF6;&#x7684;&#x663E;&#x6027;&#x81F4;&#x6B7B;&#x57FA;&#x56E0;&#x7684;&#x868A;&#x5B50;&#x6ECB;&#x751F;&#x7684;&#x91CA;&#x653E;&quot;&#x4E0D;&#x80B2;&#x7537;&#x6027;&#x91CA;&#x653E;&quot;&#x6218;&#x7565;&#x662F;&#x6709;&#x5438;&#x5F15;&#x529B;&#x7684;&#x65B0;&#x63A7;&#x5236;&#x65B9;&#x6CD5;&#x3002;&#x57C3;&#x53CA;&#x4F0A;&#x868A;&#x7684;&#x8F6C;&#x57FA;&#x56E0;&#x682A;&#x88AB;&#x5DE5;&#x7A0B;&#x6709;&#x9488;&#x5BF9;&#x5973;&#x6027; repressible &#x79CD;&#x4E0D;&#x4F1A;&#x98DE;&#x578B;&#x4F7F;&#x7528;&#x4E24;&#x4E2A;&#x5355;&#x72EC;&#x7684;&#x8F6C;&#x57FA;&#x56E0;&#x6216;&#x5355;&#x4E2A;&#x8F6C;&#x57FA;&#x56E0;&#xFF0C;&#x57FA;&#x4E8E;&#x9488;&#x5BF9;&#x5973;&#x6027;&#x7684;&#x95F4;&#x63A5;&#x98DE;&#x884C;&#x808C;&#x767D;&#x7EB9;&#x4F0A;&#x868A;&#x57C3;&#x53CA;&#x808C;&#x52A8;&#x86CB;&#x767D; 4 &#x57FA;&#x56E0;&#x542F;&#x52A8;&#x5B50;&#x7684;&#x4F7F;&#x7528;&#x3002;&#x8FD9;&#x4E9B;&#x83CC;&#x682A;&#x6D88;&#x9664;&#x8F90;&#x7167;&#x706D;&#x83CC;&#x7684;&#x5FC5;&#x8981;&#x6027;&#x3001; &#x5141;&#x8BB8;&#x6027;&#x522B; (&quot;&#x9057;&#x4F20;&#x9274;&#x5B9A;&quot;&#xFF09;&#xFF0C;&#x53EA;&#x6709;&#x7537;&#x6027;&#x624D;&#x80FD;&#x91CA;&#x653E;&#x548C;&#x542F;&#x7528;&#x91CA;&#x653E;&#x7684;&#x800C;&#x4E0D;&#x662F;&#x6210;&#x4EBA;&#x7684;&#x9E21;&#x86CB;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x8FD9;&#x4E9B;&#x83CC;&#x682A;&#x9884;&#x8BA1;&#x5C06;&#x4FC3;&#x8FDB;&#x5168;&#x533A;&#x63A7;&#x5236;&#x6216;&#x6D88;&#x9664;&#x767B;&#x9769;&#x70ED;&#x5982;&#x679C;&#x901A;&#x8FC7;&#x4F5C;&#x4E3A;&#x7EFC;&#x5408;&#x7684;&#x866B;&#x5BB3;&#x7BA1;&#x7406;&#x6218;&#x7565;&#x7684;&#x4E00;&#x90E8;&#x5206;&#x3002;

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Dengue and dengue hemorrhagic fever are increasing public health problems with an estimated 50-100 million new infections each year. Aedes aegypti is the major vector of dengue viruses in its range and control of this mosquito would reduce significantly human morbidity and mortality. Present mosquito control methods are not sufficiently effective and new approaches are needed urgently. A "sterile-male-release" strategy based on the release of mosquitoes carrying a conditional dominant lethal gene is an attractive new control methodology. Transgenic strains of Aedes aegypti were engineered to have a repressible female-specific flightless phenotype using either two separate transgenes or a single transgene, based on the use of a female-specific indirect flight muscle promoter from the Aedes aegypti Actin-4 gene. These strains eliminate the need for sterilization by irradiation, permit male-only release ("genetic sexing"), and enable the release of eggs instead of adults. Furthermore, these strains are expected to facilitate area-wide control or elimination of dengue if adopted as part of an integrated pest management strategy.

Female-specific flightless phenotype for mosquito control.

La dengue et la dengue h&#xE9;morragique sont des probl&#xE8;mes croissants de sant&#xE9; publique avec environ 50-100 millions de nouvelles infections chaque ann&#xE9;e. Aedes aegypti est le vecteur majeur de virus de la dengue dans sa gamme et le contr&#xF4;le de ce moustique serait de r&#xE9;duire la morbidit&#xE9; et la mortalit&#xE9; de fa&#xE7;on significative humaine. Pr&#xE9;senter des m&#xE9;thodes de contr&#xF4;le des moustiques ne sont pas suffisamment efficaces et de nouvelles approches sont n&#xE9;cessaires de toute urgence. Un &#xAB;m&#xE2;les st&#xE9;riles lib&#xE9;ration&#x26;quot; strat&#xE9;gie bas&#xE9;e sur la lib&#xE9;ration de moustiques porteurs d&#x26;#39;un g&#xE8;ne l&#xE9;tal dominant conditionnelle est une m&#xE9;thodologie de contr&#xF4;le attractif nouvelle. Souches transg&#xE9;niques de Aedes aegypti ont &#xE9;t&#xE9; con&#xE7;us pour avoir un ph&#xE9;notype voler r&#xE9;pressible femelle-sp&#xE9;cifique en utilisant soit deux transg&#xE8;nes distinctes ou une seule transg&#xE8;ne, sur la base de l&#x26;#39;utilisation d&#x26;#39;un promoteur sp&#xE9;cifique femelle vol musculaire indirecte de la Aedes aegypti actine-4 g&#xE8;ne. Ces souches d&#x26;#39;&#xE9;liminer la n&#xE9;cessit&#xE9; pour la st&#xE9;rilisation par irradiation, permettent exclusivement masculine de presse (&#xAB;sexage g&#xE9;n&#xE9;tique&#x26;quot;), et permettre la lib&#xE9;ration des ovules au lieu d&#x26;#39;adultes. En outre, ces souches sont cens&#xE9;s faciliter &#xE9;chelle de la zone de contr&#xF4;le ou l&#x26;#39;&#xE9;limination de la dengue si elle est adopt&#xE9;e dans le cadre d&#x26;#39;une strat&#xE9;gie de gestion int&#xE9;gr&#xE9;e des ravageurs.

Ph&#xE9;notype Flightless Femme sp&#xE9;cifique pour le contr&#xF4;le des moustiques

Denguefieber und h&auml;morrhagisches Denguefieber vermehrt Probleme im Gesundheitswesen mit einer gesch&auml;tzten 50 Millionen Neuinfektionen pro Jahr. Aedes Aegypti ist, dass die gro&szlig;en Vektor von Dengue-Viren in seinem Bereich und Kontrolle dieser M&uuml;cke deutlich menschlicher Morbidit&auml;t und Mortalit&auml;t reduzieren w&uuml;rde. Vorhanden Moskito-Control-Methoden sind nicht hinreichend wirksam und neue Ans&auml;tze werden dringend ben&ouml;tigt. Eine &quot;sterile-M&auml;nnchen-Release&quot;-Strategie basiert auf der Ver&ouml;ffentlichung von Moskitos tragen ein bedingte dominante Lethal gen ist eine attraktive neue Steuerelement-Methode. Transgene St&auml;mme von Aedes Aegypti wurden so konstruiert, dass einen repressible Weibchen-spezifische flugunf&auml;higen Ph&auml;notyp mit zwei separaten transgene oder eine einzelne Transgene, basierend auf der Verwendung von Frauen-spezifische indirekte Flug Muskel F&ouml;rderer von Aedes Aegypti Actin-4 Gen haben. Diese St&auml;mme &uuml;berfl&uuml;ssig Sterilisation durch Bestrahlung, ausschlie&szlig;lich m&auml;nnlich dominierten eingef&uuml;hrt (&quot;genetische sexing&quot;) und aktivieren die Freigabe der Eier statt Erwachsene. Dar&uuml;ber hinaus sollen diese St&auml;mme fl&auml;chendeckende Kontrolle oder Beseitigung von Dengue-Fieber wird angenommen als Teil einer Strategie des integrierten Pflanzenschutzes-Management zu erleichtern.

Weiblich-spezifische flugunf&auml;hige Ph&auml;notyp f&uuml;r Moskito-Kontrolle.

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&#x30E2;&#x30B9;&#x30AD;&#x30FC;&#x30C8;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x306E;&#x305F;&#x3081;&#x306E;&#x5973;&#x6027;&#x306E;&#x56FA;&#x6709;&#x306E;&#x98DB;&#x3079;&#x306A;&#x3044;&#x8868;&#x73FE;&#x578B;

&#xB385;&#xAE30;&#xC5F4; &#xBC0F; &#xCD9C;&#xD608; &#xC131; &#xB385;&#xAE30;&#xC5F4; &#xACF5;&#xC911; &#xBCF4;&#xAC74; &#xBB38;&#xC81C;&#xAC00; &#xC57D;&#xB41C; 50-100&#xB9CC; &#xC0C8;&#xB85C;&#xC6B4; &#xAC10;&#xC5FC; &#xB9E4;&#xB144; &#xC99D;&#xAC00; &#xD558; &#xACE0; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. Aedes aegypti &#xBC94;&#xC704;&#xC5D0;&#xC11C; &#xB385;&#xAE30;&#xC5F4; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC758; &#xC8FC;&#xC694; &#xBCA1;&#xD130; &#xBC0F;&#xC774; &#xBAA8;&#xAE30;&#xC758; &#xC81C;&#xC5B4; &#xD06C;&#xAC8C; &#xC778;&#xAC04;&#xC758; &#xBCD1; &#xC801; &#xC0C1;&#xD0DC;&#xC640; &#xC0AC;&#xB9DD;&#xB960;&#xC744; &#xC904;&#xC77C; &#xAC83; &#xC774;&#xB2E4;. &#xD604;&#xC7AC; &#xBAA8;&#xAE30; &#xC81C;&#xC5B4; &#xBC29;&#xBC95; &#xCDA9;&#xBD84;&#xD788; &#xD6A8;&#xACFC;&#xC801; &#xC774;&#xBA70; &#xC0C8;&#xB85C;&#xC6B4; &#xC811;&#xADFC; &#xAE34;&#xAE09; &#xD558; &#xAC8C; &#xD544;&#xC694; &#xD558;&#xB2E4;. &#xC870;&#xAC74;&#xBD80; &#xC9C0;&#xBC30;&#xC801;&#xC778; &#xCE58;&#xBA85;&#xC801; &#xC720;&#xC804;&#xC790;&#xB97C; &#xC6B4;&#xBC18; &#xD558;&#xB294; &#xBAA8;&#xAE30;&#xC758; &#xB9B4;&#xB9AC;&#xC2A4;&#xB97C; &#xAE30;&#xBC18;&#xC73C;&#xB85C; &#xD558;&#xB294; &quot;&#xBD88; &#xC784; &#xB0A8;&#xC131; &#xB9B4;&#xB9AC;&#xC2A4;&quot; &#xC804;&#xB7B5;&#xC740; &#xB9E4;&#xB825;&#xC801;&#xC778; &#xC0C8;&#xB85C;&#xC6B4; &#xC81C;&#xC5B4; &#xBC29;&#xBC95;&#xC785;&#xB2C8;&#xB2E4;. &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xC885;&#xC790;&#xC758; Aedes aegypti Aedes aegypti &#xB9D0;&#xB77C; 4 &#xC720;&#xC804;&#xC790;&#xC5D0;&#xC11C; &#xC5EC;&#xC131; &#xAD00;&#xB828; &#xAC04;&#xC811; &#xBE44;&#xD589; &#xADFC;&#xC721; &#xBC1C;&#xAE30;&#xC778;&#xC758; &#xC0AC;&#xC6A9;&#xC744; &#xAE30;&#xBC18;&#xC73C;&#xB85C; &#xB2E8;&#xC77C; transgene &#xB610;&#xB294; &#xB450; &#xAC1C;&#xC758; &#xBCC4;&#xB3C4; transgenes&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; repressible &#xC5EC;&#xC131; &#xACE0;&#xC720;&#xC758; &#xB0A0;&#xC9C0; &#xBABB;&#xD558;&#xB294; &#xD615;&#xC744;&#xAC00;&#xC9C0;&#xACE0; &#xC124;&#xACC4; &#xB418;&#xC5C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xBCC0;&#xC885; &#xBC29;&#xC0AC;&#xC120;&#xC73C;&#xB85C; &#xC0B4; &#xADE0;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694;&#xC131;&#xC744; &#xC81C;&#xAC70; &#xD558; &#xACE0; (&quot;&#xC720;&#xC804; &#xD30C;&#xB294;&quot;), &#xB0A8;&#xC131; &#xC804;&#xC6A9; &#xB9B4;&#xB9AC;&#xC2A4; &#xD5C8;&#xC6A9; &#xC131;&#xC778; &#xB300;&#xC2E0; &#xACC4;&#xB780;&#xC758; &#xB9B4;&#xB9AC;&#xC2A4;&#xB97C; &#xC0AC;&#xC6A9;. &#xB610;&#xD55C;, &#xC774;&#xB7EC;&#xD55C; &#xBCC0;&#xC885; &#xC601;&#xC5ED; &#xC804;&#xCCB4; &#xCEE8;&#xD2B8;&#xB864; &#xB610;&#xB294; &#xD1B5;&#xD569;&#xB41C; &#xC720;&#xD574;&#xBB3C; &#xAD00;&#xB9AC; &#xC804;&#xB7B5;&#xC758; &#xC77C;&#xD658;&#xC73C;&#xB85C; &#xCC44;&#xD0DD; &#xD558;&#xB294; &#xACBD;&#xC6B0; &#xB385;&#xAE30;&#xC5F4;&#xC758; &#xC81C;&#xAC70;&#xB97C; &#xC6A9;&#xC774; &#xD558; &#xAC8C; &#xAC83;&#xC73C;&#xB85C; &#xC608;&#xC0C1; &#xB41C;&#xB2E4;.

&#xC5EC;&#xC131; &#xAD00;&#xB828; &#xB0A0;&#xC9C0; &#xBABB;&#xD558;&#xB294; &#xD615; &#xBAA8;&#xAE30; &#xC81C;&#xC5B4;.

El dengue y la fiebre hemorr&#xE1;gica del dengue est&#xE1;n aumentando los problemas de salud p&#xFA;blica con un estimado de 50-100 millones de nuevas infecciones cada a&#xF1;o. Aedes aegypti es el principal vector del virus del dengue en su &#xE1;rea de distribuci&#xF3;n y control de este mosquito podr&#xED;a reducir la morbilidad y mortalidad humana significativa. Los actuales m&#xE9;todos de control de mosquitos no son suficientemente eficaces y los nuevos enfoques son necesarios con urgencia. A &#x26;quot;del macho est&#xE9;ril de liberaci&#xF3;n&#x26;quot; estrategia basada en la liberaci&#xF3;n de los mosquitos portadores de un gen letal dominante condicional es una metodolog&#xED;a atractiva nuevo control. Cepas transg&#xE9;nicas de Aedes aegypti fueron dise&#xF1;ados para tener un reprimible hembra espec&#xED;fica fenotipo volador ya sea utilizando dos transgenes separados o un transg&#xE9;n &#xFA;nico, basado en el uso de un promotor espec&#xED;fico hembra indirecta m&#xFA;sculo vuelo del Aedes aegypti actina-4 gen. Estas cepas eliminar la necesidad de la esterilizaci&#xF3;n por irradiaci&#xF3;n, permiten s&#xF3;lo para hombres de liberaci&#xF3;n (&#x26;quot;sexado gen&#xE9;tico&#x26;quot;), y permitir la liberaci&#xF3;n de &#xF3;vulos en lugar de adultos. Adem&#xE1;s, estas cepas se espera que facilite toda la zona de control o la eliminaci&#xF3;n del dengue si se adopta como parte de una estrategia de manejo integrado de plagas.

Espec&#xED;ficos de la mujer volador fenotipo de Control de Mosquitos

The Asian tiger mosquito, Aedes albopictus (Skuse), is a vector of several arboviruses including dengue and chikungunya. This highly invasive species originating from Southeast Asia has travelled the world in the last 30 years and is now established in Europe, North and South America, Africa, the Middle East and the Caribbean. In the absence of vaccine or antiviral drugs, efficient mosquito control strategies are crucial. Conventional control methods have so far failed to control Ae. albopictus adequately.

piggybac- and PhiC31-mediated genetic transformation of the Asian tiger mosquito, Aedes albopictus (Skuse).

Behavioral responses of Aedes aegypti male populations developed for Release of Insects Carrying a Dominant Lethal (RIDL) technology and a Malaysian wild-type population of two age groups (4-5 and 8-10 d old) were tested under laboratory conditions against chemical irritants and repellents using the high-throughput screening system device. Results indicate that all male Ae. aegypti test populations showed significant (P < 0.01) behavioral escape responses when exposed to alphacypermethrin, DDT, and deltamethrin at the test dose of 25 nmol/cm2. In addition, all populations showed significant (P < 0.05) spatial repellent responses to DDT, whereas alphacypermethrin and deltamethrin elicited no directional movement in the assay. These data suggest that genetic modification has not suppressed expected irritancy and repellency behavior. Age effects were minimal in both contact irritant and spatial repellent assays. The magnitude of irritant response, based on percentage responding, was stronger in the RIDL test cohorts as compared with the wild-type Malaysian population, but the impact, if any, that this increased behavioral sensitivity might have on the success of a RIDL strategy has yet to be defined. Information of the type reported in the current study is vital in defining the effects of genetic modification on vector behavior and understanding how these behaviors may influence the success of RIDL technology as they relate to other vector control interventions implemented in the same disease-endemic locale.

Irritant and repellent behavioral responses of Aedes aegypti male populations developed for RIDL disease control strategies.

Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.

Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections.

&#x4E00;&#x79CD;&#x57FA;&#x4E8E;&#x868A;&#x5B50;&#x643A;&#x5E26;&#x6761;&#x4EF6;&#x663E;&#x6027;&#x81F4;&#x6B7B;&#x57FA;&#x56E0; (&#x91CA;&#x653E;&#x7684;&#x6606;&#x866B;&#x643A;&#x5E26;&#x663E;&#x6027;&#x81F4;&#x6B7B;&#xFF0C;RIDL) &#x6B63;&#x5728;&#x5236;&#x8BA2;&#x63A7;&#x5236;&#x4F20;&#x64AD;&#x767B;&#x9769;&#x70ED;&#x75C5;&#x6BD2;&#x7684;&#x5411;&#x91CF;&#x4EBA;&#x53E3;&#x5236;&#x6B62;&#x3002;&#x4E00;&#x8F6C;&#x57FA;&#x56E0;&#x682A;&#xFF0C;&#x6307;&#x5B9A; OX3604C&#xFF0C;&#x4E3B;&#x8981;&#x767B;&#x9769;&#x70ED;&#x5A92;&#x4ECB;&#xFF0C;&#x57C3;&#x53CA;&#x4F0A;&#x868A;&#x7684;&#x88AB;&#x5DE5;&#x7A0B;&#xFF0C;&#x6709;&#x4E00;&#x4E2A; repressible &#x7684;&#x5973;&#x6027;&#x7279;&#x5B9A;&#x79CD;&#x8868;&#x578B;&#x3002;&#x8FD9;&#x682A;&#x7ED5;&#x8FC7;&#x8F90;&#x5C04;&#x706D;&#x83CC;&#x9700;&#x8981;&#xFF0C;&#x5141;&#x8BB8;&#x9057;&#x4F20;&#x6027;&#x522B;&#x9274;&#x5B9A;&#x7ED3;&#x679C;&#x53EA;&#x6709;&#x7537;&#x6027;&#x7684;&#x7248;&#x672C;&#x4E2D;&#xFF0C;&#x5E76;&#x5141;&#x8BB8;&#x91CA;&#x653E;&#x7684;&#x800C;&#x4E0D;&#x662F;&#x6210;&#x868A;&#x5375;&#x3002;OX3604C &#x7537;&#x6027;&#x6BCF;&#x5468;&#x5F15;&#x8FDB;&#x5927;&#x578B;&#x5B9E;&#x9A8C;&#x5BA4;&#x7B3C;&#x5B50;&#x91CC;&#x542B;&#x6709; 8.5-101 OX3604Ctarget &#x5728;&#x521D;&#x59CB;&#x6BD4;&#x7387;&#x7A33;&#x5B9A;&#x76EE;&#x6807;&#x868A;&#x5B50;&#x79CD;&#x7FA4;&#x5728; 10-20 &#x5468;&#x5185;&#x6D88;&#x9664;&#x4EBA;&#x53E3;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x652F;&#x6301;&#x7684;&#x8FDB;&#x4E00;&#x6B65;&#x6D4B;&#x8BD5;&#x4E2D;&#x6240;&#x5305;&#x542B;&#x6216;&#x5BC6;&#x95ED;&#x7530;&#x95F4;&#x8BD5;&#x9A8C;&#x8BC4;&#x4F30;&#x4EA4;&#x914D;&#x7ADE;&#x4E89;&#x529B;&#x8FD9;&#x682A;&#x548C;&#x73AF;&#x5883;&#x548C;&#x5176;&#x4ED6;&#x5F71;&#x54CD;&#x3002;&#x7530;&#x95F4;&#x8BD5;&#x9A8C;&#x7684;&#x6210;&#x529F;&#x5B8C;&#x6210;&#x5E94;&#x4FBF;&#x5229;&#x7EB3;&#x5165;&#x6B64;&#x65B9;&#x5F0F;&#x7EB3;&#x5165;&#x5168;&#x5730;&#x533A;&#x767B;&#x9769;&#x70ED;&#x63A7;&#x5236;&#x6216;&#x6D88;&#x9664;&#x52AA;&#x529B;&#x4F5C;&#x4E3A;&#x75C5;&#x5A92;&#x7EFC;&#x5408;&#x7684;&#x7BA1;&#x7406;&#x6218;&#x7565;&#x7684;&#x4E00;&#x4E2A;&#x7EC4;&#x6210;&#x90E8;&#x5206;&#x3002;

&#x767B;&#x9769;&#x70ED;&#x5A92;&#x4ECB;&#x868A;&#x866B;&#x7684;&#x9057;&#x4F20;&#x6D88;&#x9664;&#x3002;

An approach based on mosquitoes carrying a conditional dominant lethal gene (release of insects carrying a dominant lethal, RIDL) is being developed to control the transmission of dengue viruses by vector population suppression. A transgenic strain, designated OX3604C, of the major dengue vector, Aedes aegypti, was engineered to have a repressible female-specific flightless phenotype. This strain circumvents the need for radiation-induced sterilization, allows genetic sexing resulting in male-only releases, and permits the release of eggs instead of adult mosquitoes. OX3604C males introduced weekly into large laboratory cages containing stable target mosquito populations at initial ratios of 8.5-101 OX3604Ctarget eliminated the populations within 10-20Â weeks. These data support the further testing of this strain in contained or confined field trials to evaluate mating competitiveness and environmental and other effects. Successful completion of the field trials should facilitate incorporation of this approach into area-wide dengue control or elimination efforts as a component of an integrated vector management strategy.

Genetic elimination of dengue vector mosquitoes.

Une approche bas&#xE9;e sur les moustiques porteurs d&#x26;#39;un g&#xE8;ne l&#xE9;tal dominant conditionnelle (l&#xE2;chers d&#x26;#39;insectes porteurs d&#x26;#39;une mutation l&#xE9;tale dominante, RIDL) est en cours d&#x26;#39;&#xE9;laboration pour contr&#xF4;ler la transmission de virus de la dengue par la suppression des populations de vecteurs. Une souche transg&#xE9;nique, d&#xE9;sign&#xE9; OX3604C, du vecteur de la dengue majeure, Aedes aegypti, a &#xE9;t&#xE9; con&#xE7;u pour avoir un ph&#xE9;notype voler r&#xE9;pressible femelle sp&#xE9;cifique. Cette souche contourne la n&#xE9;cessit&#xE9; de radio-induite de st&#xE9;rilisation, permet de sexage g&#xE9;n&#xE9;tique r&#xE9;sultant en hommes seuls les rejets, et permet la lib&#xE9;ration des &#x153;ufs au lieu de les moustiques adultes. M&#xE2;les OX3604C introduit hebdomadaire dans des cages de laboratoire de grande taille contenant stables populations de moustiques cibles &#xE0; des taux initiaux de 8,5 &#xE0; 101 OX3604Ctarget &#xE9;limin&#xE9; les populations dans les 10-20 semaines. Ces donn&#xE9;es confirment des essais compl&#xE9;mentaires de cette souche dans les essais sur le terrain ou restreint &#xE0; &#xE9;valuer la comp&#xE9;titivit&#xE9; d&#x26;#39;accouplement et les effets environnementaux et autres. La r&#xE9;ussite des essais sur le terrain devrait faciliter l&#x26;#39;int&#xE9;gration de cette approche dans la zone de contr&#xF4;le &#xE0; l&#x26;#39;&#xE9;chelle de la dengue ou l&#x26;#39;&#xE9;limination des efforts en tant que composante d&#x26;#39;une strat&#xE9;gie de gestion int&#xE9;gr&#xE9;e des vecteurs.

&#xC9;limination g&#xE9;n&#xE9;tique des moustiques vecteurs dengue

Ein Ansatz basierend auf Moskitos tragen ein bedingte dominante Lethal-gen (Freisetzung von Insekten, die Durchf&uuml;hrung einer beherrschenden letale, RIDL) wurde entwickelt, um die &Uuml;bertragung von Dengue-Viren steuern Vektor Bev&ouml;lkerung Unterdr&uuml;ckung. Eine transgene Sorte, benannt OX3604C, des gro&szlig;en Dengue Vektors, Aedes Aegypti, wurde entwickelt, um einen repressible Weibchen-spezifische flugunf&auml;higen Ph&auml;notyp haben. Diese Sorte umgeht die Notwendigkeit der strahleninduzierten Sterilisation, genetische sexing f&uuml;hrt ausschlie&szlig;lich m&auml;nnlich dominierten Versionen erm&ouml;glicht und erlaubt die Freigabe der Eier statt K&ouml;rpergr&ouml;&szlig;e. OX3604C M&auml;nner f&uuml;hrte w&ouml;chentlich in Labor-K&auml;fige mit stabilen Moskito Zielgruppen am urspr&uuml;nglichen Verh&auml;ltnisse von 8,5-101 OX3604Ctarget eliminiert die Bev&ouml;lkerung innerhalb von 10-20 Wochen. Diese Daten unterst&uuml;tzen die weitere Pr&uuml;fung von dieser Sorte in geschlossenen oder engen Feldversuche Paarung Wettbewerbsf&auml;higkeit bewerten und Umwelt- und andere Effekte. Erfolgreichem Abschluss die Feldversuche sollte die Eingliederung dieses Ansatzes in fl&auml;chendeckenden Dengue-Steuerelement oder Beseitigung Bem&uuml;hungen als Bestandteil einer integrierten Vektor-Management-Strategie erleichtern.

Genetische Beseitigung von Dengue Vektor M&uuml;cken.

Un approccio basato sulle zanzare che trasportano un gene letale dominante condizionale (rilascio di insetti che trasportano una dominante letale, RIDL) &egrave; stato sviluppato per controllare la trasmissione del virus dengue dalla soppressione di popolazione vettoriale. Un ceppo transgenico, designato OX3604C, del vettore maggiore dengue, Aedes aegypti, &egrave; stato progettato per avere un fenotipo di flightless femmina-specifici reprensibile. Questo ceppo elude la necessit&agrave; di sterilizzazione indotta da radiazioni, genetico sexing risultante in comunicati esclusivamente maschile e permette il rilascio delle uova invece le zanzare adulte. I maschi OX3604C introdotti settimanale in gabbie di grande laboratorio contenente destinazione stabile popolazioni di zanzara a rapporti iniziali di 8,5-101 OX3604Ctarget eliminato le popolazioni entro 10-20 settimane. Questi dati supportano l&#39;ulteriore prova di questo ceppo nel contenuto o confinati prove sul campo per valutare la competitivit&agrave; degli amori e ambientali e altri effetti. Completato con successo le prove di campo dovrebbe facilitare incorporazione di questo approccio negli sforzi di controllo o l&#39;eliminazione di tutta l&#39;area dengue come componente di una strategia di gestione integrata vettoriale.

Eliminazione genetica delle zanzare vettore di dengue.

&#x6761;&#x4EF6;&#x512A;&#x6027;&#x81F4;&#x6B7B;&#x907A;&#x4F1D;&#x5B50;&#xFF08;&#x512A;&#x6027;&#x81F4;&#x6B7B;&#x3092;&#x904B;&#x3076;&#x6606;&#x866B;&#x306E;&#x30EA;&#x30EA;&#x30FC;&#x30B9;&#x3067;&#x306F;&#x3001;RIDL&#xFF09;&#x868A;&#x306B;&#x57FA;&#x3065;&#x304F;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x306F;&#x3001;&#x30D9;&#x30AF;&#x30C8;&#x30EB;&#x306E;&#x4EBA;&#x53E3;&#x6291;&#x5236;&#x306B;&#x3088;&#x308B;&#x30C7;&#x30F3;&#x30B0;&#x71B1;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x611F;&#x67D3;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x958B;&#x767A;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x4E3B;&#x8981;&#x306A;&#x30C7;&#x30F3;&#x30B0;&#x71B1;&#x30D9;&#x30AF;&#x30C8;&#x30EB;&#x3001;&#x30CD;&#x30C3;&#x30BF;&#x30A4;&#x30B7;&#x30DE;&#x30AB;&#x306E;OX3604C&#x6307;&#x5B9A;&#x3055;&#x308C;&#x305F;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30B8;&#x30A7;&#x30CB;&#x30C3;&#x30AF;&#x682A;&#x306F;&#x3001;&#x6291;&#x5236;&#x6027;&#x5973;&#x6027;&#x56FA;&#x6709;&#x306E;&#x98DB;&#x3079;&#x306A;&#x3044;&#x8868;&#x73FE;&#x578B;&#x3092;&#x6301;&#x3064;&#x3088;&#x3046;&#x306B;&#x8A2D;&#x8A08;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x3053;&#x306E;&#x682A;&#x306F;&#x3001;&#x653E;&#x5C04;&#x7DDA;&#x8A98;&#x767A;&#x6EC5;&#x83CC;&#x306E;&#x5FC5;&#x8981;&#x6027;&#x3092;&#x56DE;&#x907F;&#x3059;&#x308B;&#x7537;&#x6027;&#x306E;&#x307F;&#x306E;&#x30EA;&#x30EA;&#x30FC;&#x30B9;&#x3067;&#x306F;&#x3001;&#x7D50;&#x679C;&#x3068;&#x3057;&#x3066;&#x907A;&#x4F1D;&#x7684;&#x6027;&#x5224;&#x5225;&#x3092;&#x53EF;&#x80FD;&#x306B;&#x3057;&#x3001;&#x4EE3;&#x308F;&#x308A;&#x306B;&#x5927;&#x4EBA;&#x306E;&#x868A;&#x306E;&#x5375;&#x306E;&#x653E;&#x51FA;&#x3092;&#x53EF;&#x80FD;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002; OX3604C&#x7537;&#x6027;&#x306F;8.5&#x304B;&#x3089;101 OX3604Ctarget&#x306E;&#x521D;&#x671F;&#x6BD4;&#x3067;&#x5B89;&#x5B9A;&#x3057;&#x305F;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x306E;&#x868A;&#x306E;&#x500B;&#x4F53;&#x6570;&#x3092;&#x542B;&#x3080;&#x5927;&#x898F;&#x6A21;&#x306A;&#x5B9F;&#x9A13;&#x5BA4;&#x306E;&#x30B1;&#x30FC;&#x30B8;&#x306B;&#x6BCE;&#x9031;&#x5C0E;&#x5165;&#x3055;&#x308C;&#x305F;10&#x304B;&#x3089;20&#x9031;&#x9593;&#x4EE5;&#x5185;&#x306B;&#x96C6;&#x56E3;&#x3092;&#x6392;&#x9664;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x4EA4;&#x5C3E;&#x7AF6;&#x4E89;&#x529B;&#x3068;&#x74B0;&#x5883;&#x3084;&#x305D;&#x306E;&#x4ED6;&#x306E;&#x52B9;&#x679C;&#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x308B;&#x304B;&#x3001;&#x307E;&#x305F;&#x306F;&#x9650;&#x3089;&#x308C;&#x305F;&#x30D5;&#x30A3;&#x30FC;&#x30EB;&#x30C9;&#x8A66;&#x9A13;&#x3067;&#x306F;&#x3001;&#x3053;&#x306E;&#x682A;&#x306E;&#x3055;&#x3089;&#x306A;&#x308B;&#x30C6;&#x30B9;&#x30C8;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30D5;&#x30A3;&#x30FC;&#x30EB;&#x30C9;&#x8A66;&#x9A13;&#x306E;&#x6B63;&#x5E38;&#x306B;&#x5B8C;&#x4E86;&#x3057;&#x305F;&#x5834;&#x5408;&#x306F;&#x3001;&#x7D71;&#x5408;&#x3055;&#x308C;&#x305F;&#x30D9;&#x30AF;&#x30C8;&#x30EB;&#x306E;&#x7D4C;&#x55B6;&#x6226;&#x7565;&#x306E;&#x69CB;&#x6210;&#x8981;&#x7D20;&#x3068;&#x3057;&#x3066;&#x5730;&#x57DF;&#x5168;&#x4F53;&#x306E;&#x30C7;&#x30F3;&#x30B0;&#x71B1;&#x5236;&#x5FA1;&#x307E;&#x305F;&#x306F;&#x6392;&#x9664;&#x306E;&#x53D6;&#x308A;&#x7D44;&#x307F;&#x306B;&#x306F;&#x3001;&#x3053;&#x306E;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x306E;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x3079;&#x304D;&#x3067;&#x3042;&#x308B;&#x3002;

&#x30C7;&#x30F3;&#x30B0;&#x71B1;&#x5A92;&#x4ECB;&#x868A;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x9664;&#x53BB;

&#xC870;&#xAC74;&#xBD80; &#xC9C0;&#xBC30;&#xC801;&#xC778; &#xCE58;&#xBA85;&#xC801; &#xC720;&#xC804;&#xC790; (&#xACE4;&#xCDA9; &#xC9C0;&#xBC30; &#xCE58;&#xBA85;&#xC801;&#xC778;, RIDL &#xB4E4;&#xACE0; &#xCD9C;&#xC2DC;)&#xB97C; &#xB4E4;&#xACE0; &#xBAA8;&#xAE30;&#xB97C; &#xAE30;&#xBC18; &#xC811;&#xADFC; &#xBC29;&#xC2DD;&#xC740; &#xB385;&#xAE30;&#xC5F4; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC758; &#xC804;&#xC1A1; &#xC81C;&#xC5B4; &#xBCA1;&#xD130; &#xC778;&#xAD6C; &#xC5B5;&#xC81C;&#xC5D0; &#xC758;&#xD574; &#xAC1C;&#xBC1C; &#xB418;&#xACE0;&#xC788;&#xB2E4;. Repressible &#xC5EC;&#xC131; &#xACE0;&#xC720;&#xC758; &#xB0A0;&#xC9C0; &#xBABB;&#xD558;&#xB294; &#xD615;&#xC744; &#xC9C0;&#xC815; Aedes aegypti &#xC8FC;&#xC694; &#xB385;&#xAE30;&#xC5F4; &#xBCA1;&#xD130;&#xC758; OX3604C &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xBCC0;&#xD615; &#xC124;&#xACC4; &#xB410;&#xB2E4;. &#xC774; &#xC2A4;&#xD2B8;&#xB808;&#xC778; &#xBC29;&#xC0AC;&#xC120; &#xC720;&#xBC1C; &#xADE0;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694;&#xC131;&#xC744; &#xD53C;&#xD560; &#xC720;&#xC804; &#xB0A8;&#xC131; &#xC804;&#xC6A9; &#xC790;&#xB8CC;&#xC5D0;&#xC11C; &#xD30C;&#xB294; &#xC218; &#xACE0; &#xC131;&#xC778; &#xBAA8;&#xAE30; &#xB300;&#xC2E0; &#xACC4;&#xB780;&#xC758; &#xB9B4;&#xB9AC;&#xC2A4; &#xD569;&#xB2C8;&#xB2E4;. OX3604C &#xB0A8;&#xC131; 8.5-101 ox3604ctarget&#xC758; &#xCD08;&#xAE30; &#xBE44;&#xC728;&#xC5D0;&#xC11C; &#xC548;&#xC815;&#xC801;&#xC778; &#xB300;&#xC0C1; &#xBAA8;&#xAE30; &#xC778;&#xAD6C;&#xB97C; &#xD3EC;&#xD568; &#xD558;&#xB294; &#xB300;&#xD615; &#xC2E4;&#xD5D8;&#xC2E4; &#xC5F0;&#xC2B5;&#xC7A5;&#xC73C;&#xB85C; &#xB9E4;&#xC8FC; &#xC18C;&#xAC1C; 10-20 &#xC8FC; &#xC774;&#xB0B4;&#xC5D0; &#xC778;&#xAD6C;&#xB97C; &#xC81C;&#xAC70;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xC9DD;&#xC9D3;&#xAE30; &#xACBD;&#xC7C1;&#xB825; &#xD3C9;&#xAC00;&#xC5D0; &#xD3EC;&#xD568; &#xB41C; &#xB610;&#xB294; &#xBC00;&#xD3D0; &#xB41C; &#xD604;&#xC7A5; &#xC2E4;&#xD5D8;&#xC5D0;&#xC774; &#xAE34;&#xC7A5;&#xC758; &#xD14C;&#xC2A4;&#xD2B8; &#xCD94;&#xAC00; &#xD558; &#xACE0; &#xD658;&#xACBD; &#xBC0F; &#xAE30;&#xD0C0; &#xD6A8;&#xACFC; &#xC9C0;&#xC6D0; &#xD569;&#xB2C8;&#xB2E4;. &#xD604;&#xC7A5; &#xC2DC;&#xD5D8;&#xC758; &#xC131;&#xACF5;&#xC801;&#xC778; &#xC644;&#xB8CC; &#xD1B5;&#xD569;&#xB41C; &#xBCA1;&#xD130; &#xACBD;&#xC601; &#xC804;&#xB7B5;&#xC758; &#xAD6C;&#xC131; &#xC694;&#xC18C;&#xB85C; &#xC11C; &#xC9C0;&#xC5ED; &#xC804;&#xCCB4; &#xB385;&#xAE30;&#xC5F4; &#xC81C;&#xC5B4; &#xB610;&#xB294; &#xC81C;&#xAC70; &#xB178;&#xB825;&#xC73C;&#xB85C;&#xC774; &#xC811;&#xADFC;&#xC758; &#xC124;&#xB9BD; &#xC6A9;&#xC774; &#xD574;&#xC57C;.

&#xB385;&#xAE30;&#xC5F4; &#xBCA1;&#xD130; &#xBAA8;&#xAE30;&#xC758; &#xC720;&#xC804;&#xC790; &#xC81C;&#xAC70;&#xC785;&#xB2C8;&#xB2E4;.

Un enfoque basado en los mosquitos portadores de un gen letal dominante condicional (la liberaci&#xF3;n de los insectos portadores de una letal dominante, RIDL) est&#xE1; siendo desarrollado para controlar la transmisi&#xF3;n de los virus del dengue por la supresi&#xF3;n de vector de la poblaci&#xF3;n. Una cepa transg&#xE9;nica, designado OX3604C, del vector del dengue grave, Aedes aegypti, fue dise&#xF1;ado para tener una mujer que reprime espec&#xED;fica de fenotipo no volador. Esta cepa evita la necesidad de la radiaci&#xF3;n inducida por la esterilizaci&#xF3;n, permite el sexado gen&#xE9;tico que resulta en los hombres s&#xF3;lo versiones, y permite la liberaci&#xF3;n de &#xF3;vulos en lugar de los mosquitos adultos. Hombres OX3604C present&#xF3; semanalmente en jaulas de laboratorio que contienen grandes estables las poblaciones de mosquitos objetivo en proporciones iniciales de 8,5 a 101 OX3604Ctarget eliminado las poblaciones de un plazo de 10-20 semanas. Estos datos apoyan la prueba adicional de esta cepa en las pruebas de campo que contiene o limitarse a evaluar la competitividad de apareamiento y los efectos ambientales y de otra &#xED;ndole. La conclusi&#xF3;n con &#xE9;xito de los ensayos de campo deben facilitar la incorporaci&#xF3;n de este enfoque en los esfuerzos de control en toda la zona del dengue o la eliminaci&#xF3;n como un componente de una estrategia de manejo integrado de vectores.

Eliminaci&#xF3;n gen&#xE9;tica de los mosquitos vectores del dengue

The idea of implementing genetics-based insect control strategies modelled on the traditional SIT (Sterile Insect Technique), such as RIDL (Release of Insects carrying a Dominant Lethal), is becoming increasingly popular. In this paper, we compare a genetically modified line of Aedes aegypti carrying a tetracycline repressible, lethal positive feedback system (OX513A) with a genetically similar, unmodified counterpart and their respective responses to increasing larval rearing density using a constant amount of food per larva. The parameters that we examined were larval mortality, developmental rate (i.e., time to pupation), adult size and longevity. Analysis revealed some statistically significant differences between the life history traits we examined. The genetically modified OX513A line overall showed 5% lower larval survival as well as reduced adult longevity (20 vs 24 days mean lifespan) compared to the unmodified line. Furthermore, the OX513A line pupated about one day sooner, which could be advantageous in mass-rearing, but produced somewhat smaller adults than the unmodified line; this effect was more pronounced in females than in males. Increasing the larval rearing density delayed pupation, decreased adult longevity and reduced adult size in both lines. While the delay in pupation and the decrease in longevity were similar between the two lines, the decrease in adult size was more pronounced for OX513A males.Our study shows that in a controlled laboratory situation the transgenic sterile OX513A line may have somewhat reduced performance compared to its unmodified counterpart and that high rearing densities may further reduce performance. Laboratory-based cage trials as well as field trials are necessary to assess how the differences in life history traits documented here impact the males' success upon release. Furthermore, this paper highlights the potential value of optimisation of mass-rearing systems as optimised rearing methods may be able to alleviate performance issues associated with specific lines or with lab-adapted lines in general.

Comparison of life history characteristics of the genetically modified OX513A line and a wild type strain of Aedes aegypti.

Dengue is the most medically important arthropod-borne viral disease, with 50-100 million cases reported annually worldwide. As no licensed vaccine or dedicated therapy exists for dengue, the most promising strategies to control the disease involve targeting the predominant mosquito vector, Aedes aegypti. However, the current methods to do this are inadequate. Various approaches involving genetically engineered mosquitoes have been proposed, including the release of transgenic sterile males. However, the ability of laboratory-reared, engineered male mosquitoes to effectively compete with wild males in terms of finding and mating with wild females, which is critical to the success of these strategies, has remained untested. We report data from the first open-field trial involving a strain of engineered mosquito. We demonstrated that genetically modified male mosquitoes, released across 10 hectares for a 4-week period, mated successfully with wild females and fertilized their eggs. These findings suggest the feasibility of this technology to control dengue by suppressing field populations of A. aegypti.

Field performance of engineered male mosquitoes.

Successful suppression of a field mosquito population by sustained release of engineered male mosquitoes.

Dengue is the most important mosquito-borne viral disease. In the absence of specific drugs or vaccines, control focuses on suppressing the principal mosquito vector, Aedes aegypti, yet current methods have not proven adequate to control the disease. New methods are therefore urgently needed, for example genetics-based sterile-male-release methods. However, this requires that lab-reared, modified mosquitoes be able to survive and disperse adequately in the field.

Open field release of genetically engineered sterile male Aedes aegypti in Malaysia.

In Drosophila melanogaster the doublesex (dsx) and fruitless (fru) regulatory genes act at the bottom of the somatic sex determination pathway. Both are regulated via alternative splicing by an upstream female-specific TRA/TRA-2 complex, recognizing a common cis element. dsx controls somatic sexual differentiation of non-neural as well as of neural tissues. fru, on the other hand, expresses male-specific functions only in neural system where it is required to built the neural circuits underlying proper courtship behaviour. In the mosquito Aedes aegypti sex determination is different from Drosophila. The key male determiner M, which is located on one of a pair of homomorphic sex chromosomes, controls sex-specific splicing of the mosquito dsx orthologue. In this study we report the genomic organization and expression of the fru homologue in Ae. aegypti (Aeafru). We found that it is sex-specifically spliced suggesting that it is also under the control of the sex determination pathway. Comparative analyses between the Aeafru and Anopheles gambiae fru (Angfru) genomic loci revealed partial conservation of exon organization and extensive divergence of intron lengths. We find that Aeadsx and Aeafru share novel cis splicing regulatory elements conserved in the alternatively spliced regions. We propose that in Aedes aegypti sex-specific splicing of dsx and fru is most likely under the control of splicing regulatory factors which are different from TRA and TRA-2 found in other dipteran insects and discuss the potential use of fru and dsx for developing new genetic strategies in vector control.

The orthologue of the fruitfly sex behaviour gene fruitless in the mosquito Aedes aegypti: evolution of genomic organisation and alternative splicing.

Dengue is the most important mosquito-borne viral disease. No specific treatment or vaccine is currently available; traditional vector control methods can rarely achieve adequate control. Recently, the RIDL (Release of Insect carrying Dominant Lethality) approach has been developed, based on the sterile insect technique, in which genetically engineered 'sterile' homozygous RIDL male insects are released to mate wild females; the offspring inherit a copy of the RIDL construct and die. A RIDL strain of the dengue mosquito, Aedes aegypti, OX513A, expresses a fluorescent marker gene for identification (DsRed2) and a protein (tTAV) that causes the offspring to die. We examined whether these proteins could adversely affect predators that may feed on the insect. Aedes aegypti is a peri-domestic mosquito that typically breeds in small, rain-water-filled containers and has no specific predators. Toxorhynchites larvae feed on small aquatic organisms and are easily reared in the laboratory where they can be fed exclusively on mosquito larvae. To evaluate the effect of a predator feeding on a diet of RIDL insects, OX513A Ae. aegypti larvae were fed to two different species of Toxorhynchites (Tx. splendens and Tx. amboinensis) and effects on life table parameters of all life stages were compared to being fed on wild type larvae. No significant negative effect was observed on any life table parameter studied; this outcome and the benign nature of the expressed proteins (tTAV and DsRed2) indicate that Ae. aegypti OX513A RIDL strain is unlikely to have any adverse effects on predators in the environment.

Oral ingestion of transgenic RIDL Ae. aegypti larvae has no negative effect on two predator Toxorhynchites species.

OX513A is a transgenic strain of Aedes aegypti engineered to carry a dominant, non-sex-specific, late-acting lethal genetic system that is repressed in the presence of tetracycline. It was designed for use in a sterile-insect (SIT) pest control system called RIDL® (Release of Insects carrying a Dominant Lethal gene) by which transgenic males are released in the field to mate with wild females; in the absence of tetracycline, the progeny from such matings will not survive. We investigated the mating fitness of OX513A in the laboratory. Male OX513A were as effective as Rockefeller (ROCK) males at inducing refractoriness to further mating in wild type females and there was no reduction in their ability to inseminate multiple females. They had a lower mating success but yielded more progeny than the wild-type comparator strain (ROCK) when one male of each strain was caged with a ROCK female. Mating success and fertility of groups of 10 males-with different ratios of RIDL to ROCK-competing for five ROCK females was similar, but the median longevity of RIDL males was somewhat (18%) lower. We conclude that the fitness under laboratory conditions of OX513A males carrying a tetracycline repressible lethal gene is comparable to that of males of the wild-type comparator strain.

Fitness of transgenic mosquito Aedes aegypti males carrying a dominant lethal genetic system.

Aedes mosquitoes include important vector species such as Aedes aegypti, the major vector of dengue. Genetic control methods are being developed for several of these species, stimulated by an urgent need owing to the poor effectiveness of current methods combined with an increase in chemical pesticide resistance. In this review we discuss the various genetic strategies that have been proposed, their present status, and future prospects. We focus particularly on those methods that are already being tested in the field, including RIDL and Wolbachia-based approaches.

Derric Nimmo

Oxitec Ltd

Mass Production of Genetically Modified Aedes aegypti for Field Releases in Brazil