Resistência a Inseticidas em Mosquitos: Mecanismos e Proteínas Sensoriais SAPs

The wide distribution of insecticidetreated mosquito nets across malariaendemic regions has drastically reduced the incidence of the disease over the past 20 years and so has saved millions of lives1 However malariacarrying mosquitoes have now developed strong resistance to the pyrethroid chemicals used in these longlasting insecticidal nets LLINs2 An understanding of the mechanisms under lying resistance should reveal ways to make mosquitoes susceptible to insecticides once more On page 376 Ingham et al3 demonstrate an unexpected way in which mosquitoes in Africa neutralize pyrethroids they use a class of small proteins normally involved in chemical communication Malaria parasites are transmitted to humans by female mosquitoes of the genus Anopheles with Anopheles gambiae being a major carrier of the disease The first identified mechanism of pyrethroid resistance in wild Anopheles pop ulations was a phenomenon called knockdown resistance which involves mutations in a volt agegated sodium channel protein that reduce neuronal sensitivity to the insecticide4 Other mechanisms have also been identified includ ing enhanced metabolic activity of detoxifying enzymes such as cytochrome P450s CYPs which bind to and promote the breakdown of insecticides5 Fig 1 The emergence of strong pyrethroid resistance in West African populations of A gambiae6 prompted Ingham et al to search for more mediators of resistance The authors analysed the geneexpression profiles of insec ticideresistant A gambiae populations from Burkina Faso and Côte dIvoire To the authors surprise they discovered higherthannormal expression of genes that encode a family of chemosensory proteins called sensory appendage proteins SAPs SAPs like all chemosensory proteins are found only in insects They are small soluble proteins that typically transmit chemical signals by transporting small hydrophobic molecules between cells Ing ham and colleagues found that reducing the levels of one of these proteins SAP2 in pyrethroidresistant A gambiae significantly restored the mosquitoes susceptibility to pyre throids Conversely overexpressing SAP2 in an otherwise susceptible A gambiae colony boosted the mosquitoes resistance levels How does a chemosensory protein interfere with insecticide activity Ingham et al show that SAP2 binds to pyrethroids with high speci ficity and that its expression is enhanced in the legs of mosquitoes These data suggest that SAPs sequester pyrethroids that penetrate the mosquitos hard exterior when it lands on a bed net perhaps preventing the insecticide from exerting its toxic effect on the nervous system by promoting its breakdown Finally Ingham et al analysed the genomes of West African Anopheles populations col lected over time making use of an existing database as well as sequences that they had gathered They found that a selective sweep had occurred near the genomic region that encodes SAP2 a phenomenon in which one particular version of a genomic region becomes more prevalent in a population as a result of natural selection The authors showed that the sweep had occurred over the time in which pyrethroid resistance sharply increased maybe owing to the beneficial effects of one version of this genomic region on survival Taken together Ingham and col leagues data unveil chemosensory proteins Malaria Mosquitoes get a leg up on insecticides Flaminia Catteruccia A chemosensory protein enriched in the legs of malaria carrying mosquitoes gives them resistance to insecticides used to treat bed nets This discovery points to the challenges of tackling malaria See p376 Figure 1 Multiple lines of resistance Malariacarrying mosquitoes in West Africa have developed several mechanisms of resistance to insecticides called pyrethroids which are used to treat bed nets2 Mutations in a voltagegated sodium channel protein to which pyrethroids bind reduce the chemicals ability to recognize their target Enhanced activity of metabolic enzymes such as the cytochrome P450s CYPs can break down the pyrethroids before they kill the insect Thickening of the mosquitos outer cuticular layer can slow insecticide penetration into the skin thereby reducing the chemicals concentration Ingham et al3 now show that in the insects legs the chemosensory protein SAP2 binds to pyrethroids sequestering them and so preventing them from functioning Bed net Targetprotein resistance Metabolic resistance Cuticular resistance Chemosensory protein sequestration Pyrethroids Skin SAP2 CYP Nature Vol 577 16 January 2020 319 Expert insight into current research News views 2020 Springer Nature Lim ited All rights reserved as a key component of insecticide resistance in Anopheles mosquitoes Chemosensory proteins represent a previously unknown class of resistancecausing factor and so Ingham and coworkers find ing points to a fresh opportunity to restore full susceptibility to pyrethroids in West African Anopheles populations Resistance caused by CYP enzymes has been mitigated by adding compounds that interfere with CYPs to bed nets7 similarly compounds that inhibit binding between SAP2 and insecticides could be generated and incorporated into nextgeneration LLINs Moreover the genomic region associated with SAP2 resistance can now be used as a molecular marker for tracking the spread of this resistance mechanism In the future it will be crucial to determine whether and how chemosensory proteins interact both functionally and spatially with other mecha nisms of resistance to inform the optimal design of resistancemanagement strategies Although Ingham and coworkers study provides hope of reversing mosquitoes resistance to insecticides it also highlights how skilled these insects are at escaping unwanted attention Clearly our understand ing of insecticide resistance is far from com plete and we should expect other studies in different locations to identify yet more such mechanisms acting at local or continental levels Anopheles species have been populat ing Africa for more than 100 million years considerably longer than humans and our ancestors8 Such an enduring connection with their natural habitat is a testament to the challenge that we face when targeting these insects The next generation of LLINs and indoor residual sprays another method of delivering insecticides is currently being deployed in Africa9 Simultaneously new insecticidebased methods such as insectattractive targeted sugar baits are being tested10 But like previ ous interventions these tools will probably undergo cycles of impactful but relatively shortlived success followed by decreased effectiveness owing to the emergence of resistance Beyond insecticides other mosqui tocontrol strategies will probably encounter similar resistance issues These include meth ods that rely on mosquito killing such as mosquitocidal drugs11 and genetic systems designed to suppress Anopheles populations reviewed in ref 12 It is possible that the combined use of multiple strategies will break mosquito endurance and lead to population collapse However work from my group recently showed that strong selective pressures imposed on Anopheles females could actually favour malaria transmission for instance by trigger ing acceleration of parasite growth rates13 To avoid this issue mosquitotargeting interventions could be integrated with approaches that block parasite development in the insects without causing them harm thus reducing selective pressures Further more math ematical models suggest that our chances of achieving sustainable malaria control could be improved by incorporating antimalarials into LLINs or indoor residual sprays to kill parasites and prevent their transmission even when mosquitoes become resistant to insecticides14 Similar results could be obtained by delivering antiparasitic agents through biological or genetic means12 Whatever the eventual solution the road to malaria elimination remains long Mosquitoes are sending clear signals that they will fight for their survival Flaminia Catteruccia is in the Department of Immunology and Infectious Diseases Harvard TH Chan School of Public Health Boston Massachusetts 02115 USA email fcatterhsphharvardedu 1 Bhatt S et al Nature 526 207211 2015 2 Ranson H Lissenden N Trends Parasitol 32 187196 2016 3 Ingham V A et al Nature 577 376380 2020 4 MartinezTorres D et al Insect Mol Biol 7 179184 1998 5 Stevenson B J et al Insect Biochem Mol Biol 41 492502 2011 6 Churcher T S Lissenden N Griffin J T Worrall E Ranson H eLife 5 e16090 2016 7 Protopopoff N et al Lancet 391 15771588 2018 8 Neafsey D E et al Science 347 1258522 2015 9 NGuessan R Odjo A Ngufor C Malone D Rowland M PLoS ONE 11 e0165925 2016 10 Qualls W A et al Malar J 14 301 2015 11 Kobylinski K C et al Acta Trop 116 119126 2010 12 Shaw W R Catteruccia F Nature Microbiol 4 2034 2019 13 Werling K et al Cell 177 315325 2019 14 Paton D G et al Nature 567 239243 2019 This article was published online on 25 December 2019 Artificial intelligence AI has allowed computers to solve problems that were previ ously thought to be beyond their capabilities from defeating the best human opponents in complex games1 to automating the identifi cation of diseases2 There is therefore great interest in developing specialized circuits that can complete AI calculations faster and with lower energy consumption than can current devices On page 341 Chen et al3 demonstrate an unconventional electrical circuit in silicon that can be evolved in situ to carry out basic machinelearning operations Although computers excel at performing calculations that have welldefined answers they have not been good at making guesses For example if you are thinking about selling your car a computer is ideally suited for cal culating the average price that similar cars have sold for to help you determine your selling price But by analysing the enormous digital data sets that are currently available AI techniques such as machine learning can now teach computers to make sensible pre dictions One of the most basic operations that machinelearning algorithms can carry out when provided with a large set of inputs such as the age of a car and how many kilometres it has been driven is classification into one of a set of categories such as whether the car is in poor fair or good condition and therefore whether you can expect to get the price you want for it Using the structure of the human brain as inspiration scientists and engineers have made substantial progress in developing specialized hardware to greatly reduce the amount of time and energy needed to per form tasks such as classification4 There are also many unconventional device concepts for machine learning that are still in the early stages of development but that could offer rad ical new capabilities For example researchers are exploring whether superconductorbased electrical circuits that work at only a few degrees above absolute zero and that oper ate at gigahertz frequencies with high energy efficiency could enable machinelearning applications that are currently infeasible using conventional approaches5 Chen and coworkers circuit is also inspired by the brain and represents a major depar ture from typical electrical circuits Normally electrical current flows through circuits like water flowing in a river If the river becomes so shallow that it is reduced to a set of small Nanotechnology Evolution of circuits for machine learning Cyrus F Hirjibehedin The fundamental machinelearning task of classification can be difficult to achieve directly in ordinary computing hardware Unconventional siliconbased electrical circuits can be evolved to accomplish this task See p341 320 Nature Vol 577 16 January 2020 News views 2020 Springer Nature Lim ited All rights reserved 2020 Springer Nature Lim ited All rights reserved