Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles subpictus): Systematic Reviews Study

Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles subpictus): Systematic Reviews Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles subpictus): Systematic Reviews Study Ebrahim Abbasi, Salman Daliri This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4358998/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Anopheles subpictus is one of the main vectors of malaria in East Asia, and Australia. One of the important obstacles to fighting against this vector is knockdown resistance, which prevents the effectiveness of insecticides. Based on this, the present study was conducted to survey the resistance of Anopheles subpictus against organochlorine insecticides in the world in a systematic review. Material and methods: This study was conducted in the field of knockdown resistance, and related mutations in Anopheles subpictus against organochlorine insecticides by systematic review method. In the international databases Web of Science, Scopus, PubMed, Bioone, ProQuest, and Embase, all articles published until the end of May 2023 were extracted, and reviewed. Results: Four articles on KDR in the Anopheles subpictus were included in the systematic review process. Based on the findings, kdr in Anopheles subpictus was reported against organochlorine toxins in India, Pakistan, and Sri Lanka, but no resistance was observed in Mekong Delta. In this vector, the range of the kdr ratio was between 70 and 90%. Resistance to organochlorine pesticides was originally noted in India and then spread to Sri Lanka and Pakistan due to the L1014F mutation. Conclusions: Based on the findings, a lot of proportion of Anopheles subpictus has resistance to organochlorine insecticides and this resistance has spread to other areas where this vector operates. Hence, it is necessary to use combined insecticides to fight this vector. Knockdown Resistance Organochlorine Mosquito-Borne Diseases Anopheles Subpictus Systematic Reviews. Figures Figure 1 Introduction Anopheles subpictus is a species of Anopheles mosquito, and the vector of malaria, which is scattered via the eastern regions of Asia and Australia( 1 ). Afghanistan, Bangladesh, Australia, China, Cambodia, India, Iran, Indonesia, Maldives, Malaysia, Nepal, Myanmar (Burma), New Guinea, Pakistan, Sri Lanka, Philippines, Vietnam, Thailand, and India are among the most common areas of activity of this carrier( 2 ). An. subpictus is generally considered a potential vector in Southeast Asian countries( 3 , 4 ).. The activity of An. subpictus is more in the central regions of India and its activity decreases in the east. An. subpictus is known as a potential vector of malaria, especially in coastal areas of India and Sri Lanka( 5 , 6 ). The variable vector potential of An. subpictus in different geographical areas has led to the presence of different biological species. An. subpictus has four subspecies, A, B, C, and D, and they are identified based on paracentric inversions in X chromosome. However, the status of species identification in most countries remains ambiguous ( 2 ). A, B, C, and D subspecies were found in Sri Lanka, whereas A and B subspecies were found in India. But according to research, species B is a typical malaria vector, particularly in the coastal regions of India and Sri Lanka ( 1 , 6 ). Anopheles subpictus is the primary vector of malaria in India, and the secondary vector in Sri Lanka( 7 , 8 ). Japanese encephalitis virus has been isolated from this vector. Consequently, the control of this vector is very important to prevent the transmission of diseases. Malaria transmission can be reduced by adopting vector control measures, such as indoor residual spraying with insecticides, larval control measures, and personal protection measures ( 9 ). Installing insecticide-treated nets impregnated with persistent insecticides, treating patients simultaneously, continuously spraying with insecticides, and intermittent preventative treatment during pregnancy are some of the current malaria prevention strategies. Thus, preventive spraying is the main approach to control the vector, and prevent the spread of malaria, which protects about 40% of the population at risk ( 10 , 11 ). The World Health Organization has recommended 12 types of insecticides, in four categories: organochlorines, organophosphates, carbamates, and pyrethroids, for spraying and fighting vectors ( 12 ). Organochlorine insecticides, DDT, malathion, and synthetic pyrethroids are the most common insecticides used to fight malaria. However, the continuous and widespread use of insecticides, especially organochlorine insecticides, resulted in the development of resistance in many malaria vectors in the world ( 2 , 7 , 13 , 14 ). The mechanism of action of insecticides on carriers, especially organochlorines, and pyrethroids insecticides, is that by acting on sodium channels, they lead to the disturbances in the opening and closing of sodium channels and the death of carriers ( 15 , 16 ). Therefore, genetic mutations in target locations cause resistance in sodium channels and then resistance to insecticides. Target site insensitivity is in terms of a mutation in the voltage-sensitive sodium channel gene (Vssc). The most important of these mutations is Knockdown resistance (Kdr). Kdr mutations reduce neurosensitivity to organochlorines and pyrethroids in insects and prevent their effects on insects ( 17 – 19 ). Given that one of the primary methods for combating malaria is vector control. Insecticide resistance impedes efforts to control vectors and accelerates the development of malaria. Organochlorine insecticides are among the insecticides that are widely used in the fight against malaria in the world. As a result, resistance to them makes it difficult to fight malaria ( 2 , 20 , 21 ). In general, the presence of resistance of Anopheles subpictus against insecticides, especially organochlorine insecticides, was reported. The mutations that led to Kdr in this vector are one of the most important causes of resistance to this group of insecticides. However, the level of resistance and its extent in different regions of the world are unclear ( 22 , 23 ). Considering the importance of Anopheles subpictus as one of the main vectors of malaria and also the importance of resistance to insecticides that hinders the fight against this vector, knowing the type of resistance, and the ratio of resistance to insecticides is important for making the right decision to fight. Based on this, a study was carried out to assess the proportion of Kdr resistance to organochlorine insecticides in Anopheles subpictus and to look into the mutations discovered globally in this area using a systematic review method. Material and Methods This study was conducted using a systematic review method to evaluate knockdown resistance in Anopheles subpictus against organochlorine insecticides worldwide based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic review studies ( 24 ). The protocol of the study is registered in International Prospective Register of Systematic Review (PROSPERO) with the code CRD42021231605. Search Strategy Articles were searched without a time limit until the end of 2022 in PubMed, Web of Science, Scopus, Bioone, ProQuest, and Embase databases. Thus, all articles with medical subject headings (Mesh) and the keywords knockdown resistance, kdr, organochlorine, dichlorodiphenyltrichloroethane, DDT, deltamethrin, insecticide, insecticide susceptibility, sodium channel, malaria, and Anopheles subpictus in singular, and compound form using AND operators. and OR were searched in the title, abstract and full text of the articles. Inclusion and Exclusion Criteria Articles that have criteria: 1- Articles published in the field of resistance in Anopheles mosquito 2- Anopheles Subpictus species was studied 3- KDR resistance has been investigated. 4- Resistance to organochlorine insecticides 5- They were of good quality and were included in the study. Articles that 1- were related to other insecticides and 2- reviewed all kinds of Anopheles species (except subpictus). 3- The method of conducting the study was a review, meta-analysis, case report, or case series, and the articles that did not meet the inclusion criteria were excluded from the study. Quality Assessment To evaluate the quality of articles, the Strobe checklist (Strengthening the Reporting of Observational Studies in Epidemiology) was used. Title and abstract (1 item), introduction (2 items), study method (9 items), results (5 items), discussion (4 items), and additional things (1 item) make up the 22 elements of this checklist. The score range for this checklist is between 15 and 33, respectively. In this study, the minimum acceptable score was 20 ( 25 ). Selection of Studies Fourteen thousand three hundred and sixty-five articles were extracted during the search in scientific databases. When the retrieved articles were duplicated in Endnote software, 6859 of them were eliminated as duplicates. Following an assessment of the article titles and abstracts, 7268 articles were deemed irrelevant and were not included in the research. Finally, the full text of reviewed articles and the number of 234 articles were removed due to the not investigation of the prevalence of kdr resistance, lack of studying organochlorine insecticide, and investigation of other types of Anopheles mosquitoes (Fig. 1 ). Extracting The Data First, the title, and abstract of the articles were surveyed by two researchers independently considering the inclusion and exclusion criteria, and selected related articles. The articles' complete texts were then examined by these individuals, and those that had the necessary information were chosen and the necessary information was taken from those that did not. Data extraction was done using a pre-prepared checklist that included study location, study time, sample size, KDR resistance, and insecticide type. Results Four articles on the resistance of Anopheles subpictus to organochlorine insecticides that were conducted in India, Pakistan, Sri Lanka, and the Mekong Delta from 2009 to 2020 were included in the systematic review process. The characteristics of reviewed articles are presented in Table 1 . Table 1 The characteristics of articles included in the systematic review process Author Year of study Place of study Sample size Quality assessment (score) Surendran SN ( 26 ) 2020 Sri Lanka 141 High ( 32 ) Sing OP ( 22 ) 2015 India 24 High ( 24 ) Verhaeghen K ( 23 ) 2009 Mekong region 220 High ( 26 ) Naeem H 2019 Pakistan 260 High ( 31 ) Surendran et al. (2020) studied the resistance of Anopheles subpictus mosquito in northern Sri Lanka. To evaluate resistance to insecticides, Anopheles subpictus was collected from different habitats, and the sensitivity of adult insects to DDT, malathion, and deltamethrin was investigated. The results indicate that Anopheles subpictus is resistant to malathion, DDT, and deltamethrin. The voltage-gated sodium channel protein IIS6's transmembrane region has the L1014F (TTA to TTC) mutation, which is what causes deltamethrin resistance, according to DNA sequencing. This mutation was previously observed in India and it is the first time it was identified in Sri Lanka. Malathion bioassay showed that Anopheles subpictus was resistant to it with 95% confidence: 91%-89%. The analysis of IIS6 coding domain of the VGSC gene in Anopheles subpictus that was resistant to deltamethrin was performed in 15 sequences. which showed the presence of A to C transition and resulted in L1014F amino acid substitution (TTA to TTC) in all 15 Anopheles samples. The results revealed that the L1014F mutation was homozygous in 14 out of 15 mosquitoes ( 26 ). The L1014F-kdr mutation was examined in the Indian research by Sing et al. (2015) to assess resistance in the Anopheles subpictus . At first, to identify the L1014F-kdr mutation in Anopheles mosquitoes, a polymerase chain reaction (PIRA-PCR) was developed and used (n¼24). were sequence identical, and 100% similar to Sri Lankan "species A". IIS6 VGSC sequencing was performed targeting L1014 residue of mosquito Anopheles subpictus . DNA sequence analysis revealed the presence of two non-synonymous mutations, i.e. A > C and showed A > T at the position of the third codon residue Leu1014, both of which lead to the substitution of amino acid Leu (TTA) to Phe (TTT or TTC). TTA, TTT, and TTC allele allelic frequencies were determined to be 0.14, 0.19, and 0.67, respectively. Because of this, the combined allelic frequency of the mutant alleles (TTT and TTC) that code for the amino acid Phe was 0.86. Overall, the findings revealed that 82% of Anopheles subpictus samples had the L1014F-kdr mutation ( 22 ). Verhaeghen et al. (2009) evaluated the presence of resistance in Anopheles subpictus in the Mekong Delta. Using molecular and biochemical assays, the presence of two main mechanisms of insecticide resistance, knockdown and metabolic resistance, were investigated in the Anopheles subpictus . Two FRET/MCA assays and one PCR-RFLP were performed to screen a large number of Anopheles populations from the Mekong region for knockdown resistance (kdr), but no kdr mutations were observed in the studied species ( 23 ). Naeem et al. (2019) evaluated the resistance of Anopheles subpictus against organochlorine insecticides in Pakistan. A World Health Organization sensitivity test was utilized for this, and biochemical assays were performed to look for changed metabolic enzyme activity. In addition, wild species and species that are sensitive in a lab were included in the samples obtained. The overall average mortality rate of DDT, deltamethrin, and permethrin in field samples is 27.86% (95% confidence interval: 26.06–29.65), 44.89% (95% confidence interval: 54.46-23) respectively 43/43), and 78.82% (95% confidence interval: 6.87–82.78) were reported. Biochemical assays showed a high level of metabolic enzymes in the field population. The results showed evidence of resistance to organochlorine insecticides in field populations of Anopheles subpictus mediated by multiple metabolic mechanisms, including acetylcholinesterases, esterases, cytochrome P450, and glutathione S-transferase. To evaluate the resistance to DDT, field mosquitoes and sensitive laboratory mosquitoes were exposed to DDT for 10 to 60 minutes, the death rate in the field population was between 0 and 16%, and in the laboratory population was 90% ( 27 ). Anopheles subpictus geographic spectrum of activity, which includes Pakistan, Sri Lanka, and India, generally shows kdr against organochlorine pesticides. The L1014 mutation is the primary driver of kdr in this vector, and the resistance prevalence range has been found to be between 70% and 90%. Discussion The resistance of Anopheles mosquitoes to insecticides was reported in the distant past. The presence of resistance has led to disruption in the fight against malaria vectors and the spread of the disease. It has led to the prohibition of the use of some insecticides to fight Anopheles by World Health Organization. DDT and other organochlorine pesticides were formerly often used to combat malaria, but their effectiveness has since declined owing to Anopheles resistance. The resistance of Anopheles subpictus , which is one of the common vectors of malaria in India and East Asia, was evaluated against organochlorine insecticides. The conducted studies have reported the existence of resistance, especially the kdr type, against organochlorine insecticides, including DDT. In the past, the fight against malaria was mainly based on the use of DDT for residential spraying. About two decades after using DDT, resistance to it was reported in malaria vectors, such as Anopheles epiroticus and Anopheles subpictus in coastal areas ( 28 ). As a result, the use of DDT in the malaria control program was entirely discontinued in many regions. However, biological studies conducted in some regions after about 20 years of DDT-free use revealed that some Anopheles species that had previously been resistant to it are now sensitive to it ( 28 , 29 ). This can show that the reduction of pressure caused by not using insecticides in the long term can lead to a reduction or complete elimination of resistance against them ( 30 ). Insects can survive the toxic effects of insecticides by various physiological mechanisms, including target site desensitization, and increased detoxification enzyme production. As kdr is the most important type of resistance caused by insensitivity to target site, kdr mutations are increasing rapidly, and frequently in many different Anopheles species resistant to organochlorine toxins, including DDT, in different geographical areas ( 31 , 32 ). kdr is caused by genetic mutations in Anopheles , L1014F being the most commonly reported mutation (among the mutations reported in VGSC) in a wide array of insects of sanitary importance, leading to kdr ( 33 ). In the majority of identified Anopheles, the L1014 gene is encoded by TTA. The L1014F mutation is supplanted at the third codon position by an A > T mutation. The A > C mutation, which is extremely uncommon in insects and was reported for the first time in India in the Anopheles subpictus , is a recent nucleotide substitution that leads to the L1014F mutation. A > C mutation in this species is dominant over the A > T mutation and can lead to kdr. The presence of two different types of mutations in a population may be in terms of two independent origins of mutations in an admixed population or two inbreeding populations. The absence of variation in Rdna, and the absence of polymorphism in the VGSC intron downstream of the L1014 locus indicate the presence of different species by random mating or genetic exchange ( 22 ). In general, in the studies conducted, the L1014F mutation is the main cause of Anopheles resistance to insecticides, and the rate of resistance has increased over many years ( 34 , 35 ). In many countries, in terms of insect resistance to DDT, pyrethroids have replaced other insecticides and are widely used for maintenance spraying, and combating agricultural pests ( 36 ). Widespread use of insecticides for agriculture leads to the selection pressure against insecticides in endemic areas of malaria and increasing resistance to them ( 37 , 38 ). An evaluation of the sensitivity of Anopheles subpictus against pyrethroids, organophosphates, and organochlorine in Pakistan showed that the resistance to insecticides in Anopheles subpictus is due to the selection pressure caused by continuous exposure to them ( 39 ). In addition, the presence of extremely high resistance in this vector indicates that the resistance factor against DDT has been maintained for decades after its use was discontinued ( 40 ). Stabilization of resistant alleles may be one of the primary causes of DDT resistance persistence in malaria vectors ( 9 , 41 ). The involvement of biochemical mechanisms can play an essential role in causing or not poisoning insecticides. The high level of GST (Glutathione S-transferase) in resistant mosquitoes indicates the possibility of GST involvement in DDT detoxification in mosquitoes and their resistance ( 42 , 43 ). In general, Anopheles subpictus is resistant to organochlorine insecticides in the areas where this vector operates, and this resistance was stabled for a long time. Various factors, such as genetic mutations, and metabolic and chemical changes can play a role to create resistance in this vector. Consequently, to combat this vector, it is necessary to first check its sensitivity to insecticides and by determining the effectiveness of insecticides, choose the appropriate insecticide to combat it and prevent the occurrence of resistance to other insecticides. Conclusion Based on the findings, a large proportion of Anopheles subpictus are resistant to organochlorine insecticides, and this resistance has spread to other areas where this vector is. The primary causes of resistance in this vector are genetic modifications and target site mutations. Given that this vector is one of the primary vectors for transmitting malaria, it is advised to employ appropriate or combination insecticides to combat this vector by determining its susceptibility to insecticides in various locations. Declarations Ethics approval and consent to participate Not applicable. Data Availability Statement All data generated or analysed during this study are included in this published article. Competing interests The authors declare no competing interests. Consent for publication Not applicable Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors' contributions. EA determined the title, wrote and registered the protocol, and submitted the article. EA and SD extracted the files from the databases. EA and SD, screening, and selection of final reports. EA, data extraction. SD wrote the article. All authors read and approved the final manuscript. 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Annals of Tropical Medicine & Parasitology. 1986;80(1):69-75. Perera MDB, Hemingway J, Karunaratne S. Multiple insecticide resistance mechanisms involving metabolic changes and insensitive target sites selected in anopheline vectors of malaria in Sri Lanka. Malaria Journal. 2008;7(1):1-10. Che-Mendoza A, Penilla RP, Rodríguez DA. Insecticide resistance and glutathione S-transferases in mosquitoes: A review. African Journal of Biotechnology. 2009;8(8). Surendran SN, Jude PJ, Weerarathne TC, Parakrama Karunaratne S, Ramasamy R. Variations in susceptibility to common insecticides and resistance mechanisms among morphologically identified sibling species of the malaria vector Anopheles subpictus in Sri Lanka. Parasites & vectors. 2012;5(1):1-9. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4358998","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298671293,"identity":"1c7da151-efa3-46d3-8878-d79c1a4b64ed","order_by":0,"name":"Ebrahim Abbasi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie2PMUvEMBTHHxRuCnStBNpPILxSuEWp38K5RyFdInR07OTWXYjgV1CEmyMF3W6OpIP3DSouFQ80OU7BIZXbBPMbwv+F9+PPA/B4/iIRMQ/aABCYENtP+byPkm2V4lcFvhSARWOHKSUU7f3LWB9DSNv1a10vq+vTbm1a8viwcZT0q5ISZHBw9ZjRS9Rnt5qhUcpsLh01iiMF7AAVA+MaRRRWkYulQ0kUz95G/IATxYJ3o1SpqIZJBRWfRwQlYMRmtqVIKJ9uSfsVOyJYkqh/mJmg0xvKa1mg+5ZYt93TuMnjUFwEmmx0kojqbhjO89h5/g7ynXC7idPrP0mafbY9Ho/nP/AJtKpeJRlziCkAAAAASUVORK5CYII=","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Ebrahim","middleName":"","lastName":"Abbasi","suffix":""},{"id":298671295,"identity":"9c60f85b-2997-4c5b-aab5-06a3aedeef91","order_by":1,"name":"Salman Daliri","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Salman","middleName":"","lastName":"Daliri","suffix":""}],"badges":[],"createdAt":"2024-05-02 11:56:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4358998/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4358998/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56059736,"identity":"dae36438-939e-4bcc-b5d5-5d9451fdbc94","added_by":"auto","created_at":"2024-05-08 04:27:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42709,"visible":true,"origin":"","legend":"\u003cp\u003eThePRISMA flow diagram of the search process\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4358998/v1/131e2ca374f6e3377ca36239.png"},{"id":56060601,"identity":"af1fdf38-6b6f-4502-a977-9ef4b7c81827","added_by":"auto","created_at":"2024-05-08 04:43:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":422132,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4358998/v1/1a67ec9d-da09-4f33-9b1a-52d4eb1e1a0e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles subpictus): Systematic Reviews Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eAnopheles subpictus\u003c/em\u003e is a species of \u003cem\u003eAnopheles\u003c/em\u003e mosquito, and the vector of malaria, which is scattered via the eastern regions of Asia and Australia(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Afghanistan, Bangladesh, Australia, China, Cambodia, India, Iran, Indonesia, Maldives, Malaysia, Nepal, Myanmar (Burma), New Guinea, Pakistan, Sri Lanka, Philippines, Vietnam, Thailand, and India are among the most common areas of activity of this carrier(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). \u003cem\u003eAn. subpictus\u003c/em\u003e is generally considered a potential vector in Southeast Asian countries(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).. The activity of \u003cem\u003eAn. subpictus\u003c/em\u003e is more in the central regions of India and its activity decreases in the east. \u003cem\u003eAn. subpictus\u003c/em\u003e is known as a potential vector of malaria, especially in coastal areas of India and Sri Lanka(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The variable vector potential of \u003cem\u003eAn. subpictus\u003c/em\u003e in different geographical areas has led to the presence of different biological species. \u003cem\u003eAn. subpictus\u003c/em\u003e has four subspecies, A, B, C, and D, and they are identified based on paracentric inversions in X chromosome. However, the status of species identification in most countries remains ambiguous (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). A, B, C, and D subspecies were found in Sri Lanka, whereas A and B subspecies were found in India. But according to research, species B is a typical malaria vector, particularly in the coastal regions of India and Sri Lanka (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). \u003cem\u003eAnopheles subpictus\u003c/em\u003e is the primary vector of malaria in India, and the secondary vector in Sri Lanka(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Japanese encephalitis virus has been isolated from this vector. Consequently, the control of this vector is very important to prevent the transmission of diseases. Malaria transmission can be reduced by adopting vector control measures, such as indoor residual spraying with insecticides, larval control measures, and personal protection measures (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Installing insecticide-treated nets impregnated with persistent insecticides, treating patients simultaneously, continuously spraying with insecticides, and intermittent preventative treatment during pregnancy are some of the current malaria prevention strategies. Thus, preventive spraying is the main approach to control the vector, and prevent the spread of malaria, which protects about 40% of the population at risk (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The World Health Organization has recommended 12 types of insecticides, in four categories: organochlorines, organophosphates, carbamates, and pyrethroids, for spraying and fighting vectors (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Organochlorine insecticides, DDT, malathion, and synthetic pyrethroids are the most common insecticides used to fight malaria. However, the continuous and widespread use of insecticides, especially organochlorine insecticides, resulted in the development of resistance in many malaria vectors in the world (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe mechanism of action of insecticides on carriers, especially organochlorines, and pyrethroids insecticides, is that by acting on sodium channels, they lead to the disturbances in the opening and closing of sodium channels and the death of carriers (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Therefore, genetic mutations in target locations cause resistance in sodium channels and then resistance to insecticides. Target site insensitivity is in terms of a mutation in the voltage-sensitive sodium channel gene (Vssc). The most important of these mutations is Knockdown resistance (Kdr). Kdr mutations reduce neurosensitivity to organochlorines and pyrethroids in insects and prevent their effects on insects (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Given that one of the primary methods for combating malaria is vector control. Insecticide resistance impedes efforts to control vectors and accelerates the development of malaria. Organochlorine insecticides are among the insecticides that are widely used in the fight against malaria in the world. As a result, resistance to them makes it difficult to fight malaria (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn general, the presence of resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e against insecticides, especially organochlorine insecticides, was reported. The mutations that led to Kdr in this vector are one of the most important causes of resistance to this group of insecticides. However, the level of resistance and its extent in different regions of the world are unclear (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Considering the importance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e as one of the main vectors of malaria and also the importance of resistance to insecticides that hinders the fight against this vector, knowing the type of resistance, and the ratio of resistance to insecticides is important for making the right decision to fight. Based on this, a study was carried out to assess the proportion of Kdr resistance to organochlorine insecticides in \u003cem\u003eAnopheles subpictus\u003c/em\u003e and to look into the mutations discovered globally in this area using a systematic review method.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eThis study was conducted using a systematic review method to evaluate knockdown resistance in \u003cem\u003eAnopheles subpictus\u003c/em\u003e against organochlorine insecticides worldwide based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic review studies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The protocol of the study is registered in International Prospective Register of Systematic Review (PROSPERO) with the code CRD42021231605.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy\u003c/h2\u003e \u003cp\u003eArticles were searched without a time limit until the end of 2022 in PubMed, Web of Science, Scopus, Bioone, ProQuest, and Embase databases. Thus, all articles with medical subject headings (Mesh) and the keywords knockdown resistance, kdr, organochlorine, dichlorodiphenyltrichloroethane, DDT, deltamethrin, insecticide, insecticide susceptibility, sodium channel, malaria, and \u003cem\u003eAnopheles subpictus\u003c/em\u003e in singular, and compound form using AND operators. and OR were searched in the title, abstract and full text of the articles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003eArticles that have criteria: 1- Articles published in the field of resistance in Anopheles mosquito 2- \u003cem\u003eAnopheles Subpictus\u003c/em\u003e species was studied 3- KDR resistance has been investigated. 4- Resistance to organochlorine insecticides 5- They were of good quality and were included in the study. Articles that 1- were related to other insecticides and 2- reviewed all kinds of \u003cem\u003eAnopheles\u003c/em\u003e species (except subpictus). 3- The method of conducting the study was a review, meta-analysis, case report, or case series, and the articles that did not meet the inclusion criteria were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eTo evaluate the quality of articles, the Strobe checklist (Strengthening the Reporting of Observational Studies in Epidemiology) was used. Title and abstract (1 item), introduction (2 items), study method (9 items), results (5 items), discussion (4 items), and additional things (1 item) make up the 22 elements of this checklist. The score range for this checklist is between 15 and 33, respectively. In this study, the minimum acceptable score was 20 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSelection of Studies\u003c/h2\u003e \u003cp\u003eFourteen thousand three hundred and sixty-five articles were extracted during the search in scientific databases. When the retrieved articles were duplicated in Endnote software, 6859 of them were eliminated as duplicates. Following an assessment of the article titles and abstracts, 7268 articles were deemed irrelevant and were not included in the research. Finally, the full text of reviewed articles and the number of 234 articles were removed due to the not investigation of the prevalence of kdr resistance, lack of studying organochlorine insecticide, and investigation of other types of Anopheles mosquitoes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eExtracting The Data\u003c/h2\u003e \u003cp\u003eFirst, the title, and abstract of the articles were surveyed by two researchers independently considering the inclusion and exclusion criteria, and selected related articles. The articles' complete texts were then examined by these individuals, and those that had the necessary information were chosen and the necessary information was taken from those that did not. Data extraction was done using a pre-prepared checklist that included study location, study time, sample size, KDR resistance, and insecticide type.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFour articles on the resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e to organochlorine insecticides that were conducted in India, Pakistan, Sri Lanka, and the Mekong Delta from 2009 to 2020 were included in the systematic review process. The characteristics of reviewed articles are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe characteristics of articles included in the systematic review process\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear of study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlace of study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQuality assessment (score)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurendran SN (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSri Lanka\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHigh (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSing OP (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHigh (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerhaeghen K (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMekong region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHigh (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNaeem H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePakistan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHigh (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSurendran et al. (2020) studied the resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e mosquito in northern Sri Lanka. To evaluate resistance to insecticides, \u003cem\u003eAnopheles subpictus\u003c/em\u003e was collected from different habitats, and the sensitivity of adult insects to DDT, malathion, and deltamethrin was investigated. The results indicate that Anopheles subpictus is resistant to malathion, DDT, and deltamethrin. The voltage-gated sodium channel protein IIS6's transmembrane region has the L1014F (TTA to TTC) mutation, which is what causes deltamethrin resistance, according to DNA sequencing. This mutation was previously observed in India and it is the first time it was identified in Sri Lanka. Malathion bioassay showed that \u003cem\u003eAnopheles subpictus\u003c/em\u003e was resistant to it with 95% confidence: 91%-89%. The analysis of IIS6 coding domain of the VGSC gene in \u003cem\u003eAnopheles subpictus\u003c/em\u003e that was resistant to deltamethrin was performed in 15 sequences. which showed the presence of A to C transition and resulted in L1014F amino acid substitution (TTA to TTC) in all 15 \u003cem\u003eAnopheles\u003c/em\u003e samples. The results revealed that the L1014F mutation was homozygous in 14 out of 15 mosquitoes (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The L1014F-kdr mutation was examined in the Indian research by Sing et al. (2015) to assess resistance in the \u003cem\u003eAnopheles subpictus\u003c/em\u003e. At first, to identify the L1014F-kdr mutation in \u003cem\u003eAnopheles\u003c/em\u003e mosquitoes, a polymerase chain reaction (PIRA-PCR) was developed and used (n\u0026frac14;24). were sequence identical, and 100% similar to Sri Lankan \"species A\". IIS6 VGSC sequencing was performed targeting L1014 residue of mosquito \u003cem\u003eAnopheles subpictus\u003c/em\u003e. DNA sequence analysis revealed the presence of two non-synonymous mutations, i.e. A\u0026thinsp;\u0026gt;\u0026thinsp;C and showed A\u0026thinsp;\u0026gt;\u0026thinsp;T at the position of the third codon residue Leu1014, both of which lead to the substitution of amino acid Leu (TTA) to Phe (TTT or TTC). TTA, TTT, and TTC allele allelic frequencies were determined to be 0.14, 0.19, and 0.67, respectively. Because of this, the combined allelic frequency of the mutant alleles (TTT and TTC) that code for the amino acid Phe was 0.86. Overall, the findings revealed that 82% of \u003cem\u003eAnopheles subpictus\u003c/em\u003e samples had the L1014F-kdr mutation (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Verhaeghen et al. (2009) evaluated the presence of resistance in \u003cem\u003eAnopheles subpictus\u003c/em\u003e in the Mekong Delta. Using molecular and biochemical assays, the presence of two main mechanisms of insecticide resistance, knockdown and metabolic resistance, were investigated in the \u003cem\u003eAnopheles subpictus\u003c/em\u003e. Two FRET/MCA assays and one PCR-RFLP were performed to screen a large number of \u003cem\u003eAnopheles\u003c/em\u003e populations from the Mekong region for knockdown resistance (kdr), but no kdr mutations were observed in the studied species (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Naeem et al. (2019) evaluated the resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e against organochlorine insecticides in Pakistan. A World Health Organization sensitivity test was utilized for this, and biochemical assays were performed to look for changed metabolic enzyme activity. In addition, wild species and species that are sensitive in a lab were included in the samples obtained. The overall average mortality rate of DDT, deltamethrin, and permethrin in field samples is 27.86% (95% confidence interval: 26.06\u0026ndash;29.65), 44.89% (95% confidence interval: 54.46-23) respectively 43/43), and 78.82% (95% confidence interval: 6.87\u0026ndash;82.78) were reported. Biochemical assays showed a high level of metabolic enzymes in the field population. The results showed evidence of resistance to organochlorine insecticides in field populations of \u003cem\u003eAnopheles subpictus\u003c/em\u003e mediated by multiple metabolic mechanisms, including acetylcholinesterases, esterases, cytochrome P450, and glutathione S-transferase. To evaluate the resistance to DDT, field mosquitoes and sensitive laboratory mosquitoes were exposed to DDT for 10 to 60 minutes, the death rate in the field population was between 0 and 16%, and in the laboratory population was 90% (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eAnopheles subpictus\u003c/em\u003e geographic spectrum of activity, which includes Pakistan, Sri Lanka, and India, generally shows kdr against organochlorine pesticides. The L1014 mutation is the primary driver of kdr in this vector, and the resistance prevalence range has been found to be between 70% and 90%.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe resistance of \u003cem\u003eAnopheles\u003c/em\u003e mosquitoes to insecticides was reported in the distant past. The presence of resistance has led to disruption in the fight against malaria vectors and the spread of the disease. It has led to the prohibition of the use of some insecticides to fight \u003cem\u003eAnopheles\u003c/em\u003e by World Health Organization. DDT and other organochlorine pesticides were formerly often used to combat malaria, but their effectiveness has since declined owing to Anopheles resistance. The resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e, which is one of the common vectors of malaria in India and East Asia, was evaluated against organochlorine insecticides. The conducted studies have reported the existence of resistance, especially the kdr type, against organochlorine insecticides, including DDT.\u003c/p\u003e \u003cp\u003eIn the past, the fight against malaria was mainly based on the use of DDT for residential spraying. About two decades after using DDT, resistance to it was reported in malaria vectors, such as \u003cem\u003eAnopheles epiroticus\u003c/em\u003e and \u003cem\u003eAnopheles subpictus\u003c/em\u003e in coastal areas (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). As a result, the use of DDT in the malaria control program was entirely discontinued in many regions. However, biological studies conducted in some regions after about 20 years of DDT-free use revealed that some Anopheles species that had previously been resistant to it are now sensitive to it (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). This can show that the reduction of pressure caused by not using insecticides in the long term can lead to a reduction or complete elimination of resistance against them (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Insects can survive the toxic effects of insecticides by various physiological mechanisms, including target site desensitization, and increased detoxification enzyme production. As kdr is the most important type of resistance caused by insensitivity to target site, kdr mutations are increasing rapidly, and frequently in many different \u003cem\u003eAnopheles\u003c/em\u003e species resistant to organochlorine toxins, including DDT, in different geographical areas (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). kdr is caused by genetic mutations in \u003cem\u003eAnopheles\u003c/em\u003e, L1014F being the most commonly reported mutation (among the mutations reported in VGSC) in a wide array of insects of sanitary importance, leading to kdr (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In the majority of identified Anopheles, the L1014 gene is encoded by TTA. The L1014F mutation is supplanted at the third codon position by an A\u0026thinsp;\u0026gt;\u0026thinsp;T mutation. The A\u0026thinsp;\u0026gt;\u0026thinsp;C mutation, which is extremely uncommon in insects and was reported for the first time in India in the \u003cem\u003eAnopheles subpictus\u003c/em\u003e, is a recent nucleotide substitution that leads to the L1014F mutation. A\u0026thinsp;\u0026gt;\u0026thinsp;C mutation in this species is dominant over the A\u0026thinsp;\u0026gt;\u0026thinsp;T mutation and can lead to kdr. The presence of two different types of mutations in a population may be in terms of two independent origins of mutations in an admixed population or two inbreeding populations. The absence of variation in Rdna, and the absence of polymorphism in the VGSC intron downstream of the L1014 locus indicate the presence of different species by random mating or genetic exchange (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In general, in the studies conducted, the L1014F mutation is the main cause of \u003cem\u003eAnopheles\u003c/em\u003e resistance to insecticides, and the rate of resistance has increased over many years (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn many countries, in terms of insect resistance to DDT, pyrethroids have replaced other insecticides and are widely used for maintenance spraying, and combating agricultural pests (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Widespread use of insecticides for agriculture leads to the selection pressure against insecticides in endemic areas of malaria and increasing resistance to them (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). An evaluation of the sensitivity of \u003cem\u003eAnopheles subpictus\u003c/em\u003e against pyrethroids, organophosphates, and organochlorine in Pakistan showed that the resistance to insecticides in \u003cem\u003eAnopheles subpictus\u003c/em\u003e is due to the selection pressure caused by continuous exposure to them (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). In addition, the presence of extremely high resistance in this vector indicates that the resistance factor against DDT has been maintained for decades after its use was discontinued (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Stabilization of resistant alleles may be one of the primary causes of DDT resistance persistence in malaria vectors (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). The involvement of biochemical mechanisms can play an essential role in causing or not poisoning insecticides. The high level of GST (Glutathione S-transferase) in resistant mosquitoes indicates the possibility of GST involvement in DDT detoxification in mosquitoes and their resistance (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). In general, \u003cem\u003eAnopheles subpictus\u003c/em\u003e is resistant to organochlorine insecticides in the areas where this vector operates, and this resistance was stabled for a long time. Various factors, such as genetic mutations, and metabolic and chemical changes can play a role to create resistance in this vector. Consequently, to combat this vector, it is necessary to first check its sensitivity to insecticides and by determining the effectiveness of insecticides, choose the appropriate insecticide to combat it and prevent the occurrence of resistance to other insecticides.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on the findings, a large proportion of \u003cem\u003eAnopheles subpictus\u003c/em\u003e are resistant to organochlorine insecticides, and this resistance has spread to other areas where this vector is. The primary causes of resistance in this vector are genetic modifications and target site mutations. Given that this vector is one of the primary vectors for transmitting malaria, it is advised to employ appropriate or combination insecticides to combat this vector by determining its susceptibility to insecticides in various locations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003cbr\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions.\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;EA determined the title, wrote and registered the protocol, and submitted the article. EA and SD extracted the files from the databases. EA and SD, screening, and selection of final reports. EA, data extraction. SD wrote the article. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSindhania A, Das MK, Sharma G, Surendran SN, Kaushal B, Lohani HP, et al. Molecular forms of Anopheles subpictus and Anopheles sundaicus in the Indian subcontinent. Malaria Journal. 2020;19(1):1-17.\u003c/li\u003e\n\u003cli\u003eChandra G, Bhattacharjee I, Chatterjee S. A review on Anopheles subpictus Grassi\u0026mdash;a biological vector. Acta tropica. 2010;115(1-2):142-54.\u003c/li\u003e\n\u003cli\u003eCooper RD, Edstein MD, Frances SP, Beebe NW. Malaria vectors of timor-leste. Malaria Journal. 2010;9:1-11.\u003c/li\u003e\n\u003cli\u003eNdoen E, Wild C, Dale P, Sipe N, Dale M. Relationships between anopheline mosquitoes and topography in West Timor and Java, Indonesia. 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Evaluation of resistance of human head lice to pyrethroid insecticides: a meta-analysis study. medRxiv. 2022:2022.08. 04.22278398.\u003c/li\u003e\n\u003cli\u003eRinkevich FD, Du Y, Dong K. Diversity and convergence of sodium channel mutations involved in resistance to pyrethroids. Pesticide biochemistry and physiology. 2013;106(3):93-100.\u003c/li\u003e\n\u003cli\u003eTakken W. Do insecticide‐treated bednets have an effect on malaria vectors? Tropical Medicine \u0026amp; International Health. 2002;7(12):1022-30.\u003c/li\u003e\n\u003cli\u003eAbbasi E, Vahedi M, Bagheri M, Gholizadeh S, Alipour H, Moemenbellah-Fard MD. Monitoring of synthetic insecticides resistance and mechanisms among malaria vector mosquitoes in Iran: A systematic review. Heliyon. 2022:e08830.\u003c/li\u003e\n\u003cli\u003eSingh O, Dykes C, Sharma G, Das M. L1014F-kdr mutation in Indian Anopheles subpictus (Diptera: Culicidae) arising from two alternative transversions in the voltage-gated sodium channel and a single PIRA-PCR for their detection. Journal of medical entomology. 2015;52(1):24-7.\u003c/li\u003e\n\u003cli\u003eVerhaeghen K, Van Bortel W, Trung HD, Sochantha T, Coosemans M. Absence of knockdown resistance suggests metabolic resistance in the main malaria vectors of the Mekong region. Malaria journal. 2009;8:1-14.\u003c/li\u003e\n\u003cli\u003eMoher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 2015;4(1):1.\u003c/li\u003e\n\u003cli\u003eVon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. 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The insecticide resistance status of malaria vectors in the Mekong region. Malaria journal. 2008;7(1):1-15.\u003c/li\u003e\n\u003cli\u003eHung DQ, Thiemann W. Contamination by selected chlorinated pesticides in surface waters in Hanoi, Vietnam. Chemosphere. 2002;47(4):357-67.\u003c/li\u003e\n\u003cli\u003eKarunaratne S, Hawkes NJ, Perera M, Ranson H, Hemingway J. Mutated sodium channel genes and elevated monooxygenases are found in pyrethroid resistant populations of Sri Lankan malaria vectors. Pesticide Biochemistry and Physiology. 2007;88(1):108-13.\u003c/li\u003e\n\u003cli\u003eKim H, Baek JH, Lee W-J, Lee SH. Frequency detection of pyrethroid resistance allele in Anopheles sinensis populations by real-time PCR amplification of specific allele (rtPASA). Pesticide biochemistry and physiology. 2007;87(1):54-61.\u003c/li\u003e\n\u003cli\u003eKang S, Jung J, Lee S, Hwang H, Kim W. The polymorphism and the geographical distribution of the knockdown resistance (kdr) of Anopheles sinensis in the Republic of Korea. Malaria Journal. 2012;11(1):1-8.\u003c/li\u003e\n\u003cli\u003eSingh OP, Dykes CL, Lather M, Agrawal OP, Adak T. Knockdown resistance (kdr)-like mutations in the voltage-gated sodium channel of a malaria vector Anopheles stephensi and PCR assays for their detection. Malaria journal. 2011;10:1-7.\u003c/li\u003e\n\u003cli\u003eSingh OP, Bali P, Hemingway J, Subbarao SK, Dash AP, Adak T. PCR-based methods for the detection of L1014 kdr mutation in Anopheles culicifacies sensu lato. Malaria journal. 2009;8:1-8.\u003c/li\u003e\n\u003cli\u003eJahan N, Shahid A. Evaluation of resistance against deltamethrin and cypermethrin in dengue vector from Lahore, Pakistan. J Anim Plant Sci. 2013;23(5):1321-6.\u003c/li\u003e\n\u003cli\u003eRathor HR, Nadeem G, Khan IA. Pesticide susceptibility status of Anopheles mosquitoes in four flood-affected districts of South Punjab, Pakistan. Vector-Borne and Zoonotic Diseases. 2013;13(1):60-6.\u003c/li\u003e\n\u003cli\u003eMallah GH. Review of the current status of insecticide resistance in insect pests of cotton and their management. Pak J Bot. 2007;39(7):2699-703.\u003c/li\u003e\n\u003cli\u003eHammad M, Ahmed N, Khan IA, Shah B, Kan A, Ali M, et al. Studies on the efficacy of selected insecticides against Anopheles mosquitoes of village Goth Bhoorji (Sindh) Pakistan. J Entomol Zool Studies. 2015;3:169-73.\u003c/li\u003e\n\u003cli\u003eReisen W. Population dynamics of some Pakistan mosquitoes: the impact of residual organophosphate insecticide spray on anopheline relative abundance. Annals of Tropical Medicine \u0026amp; Parasitology. 1986;80(1):69-75.\u003c/li\u003e\n\u003cli\u003ePerera MDB, Hemingway J, Karunaratne S. Multiple insecticide resistance mechanisms involving metabolic changes and insensitive target sites selected in anopheline vectors of malaria in Sri Lanka. Malaria Journal. 2008;7(1):1-10.\u003c/li\u003e\n\u003cli\u003eChe-Mendoza A, Penilla RP, Rodr\u0026iacute;guez DA. Insecticide resistance and glutathione S-transferases in mosquitoes: A review. African Journal of Biotechnology. 2009;8(8).\u003c/li\u003e\n\u003cli\u003eSurendran SN, Jude PJ, Weerarathne TC, Parakrama Karunaratne S, Ramasamy R. Variations in susceptibility to common insecticides and resistance mechanisms among morphologically identified sibling species of the malaria vector Anopheles subpictus in Sri Lanka. Parasites \u0026amp; vectors. 2012;5(1):1-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Knockdown Resistance, Organochlorine, Mosquito-Borne Diseases, Anopheles Subpictus, Systematic Reviews.","lastPublishedDoi":"10.21203/rs.3.rs-4358998/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4358998/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e \u003cem\u003eAnopheles subpictus\u003c/em\u003e is one of the main vectors of malaria in East Asia, and Australia. One of the important obstacles to fighting against this vector is knockdown resistance, which prevents the effectiveness of insecticides. Based on this, the present study was conducted to survey the resistance of \u003cem\u003eAnopheles subpictus\u003c/em\u003e against organochlorine insecticides in the world in a systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and methods:\u003c/strong\u003e This study was conducted in the field of knockdown resistance, and related mutations in \u003cem\u003eAnopheles subpictus\u003c/em\u003eagainst organochlorine insecticides by systematic review method. In the international databases Web of Science, Scopus, PubMed, Bioone, ProQuest, and Embase, all articles published until the end of May 2023 were extracted, and reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Four articles on KDR in the \u003cem\u003eAnopheles subpictus\u003c/em\u003ewere included in the systematic review process. Based on the findings, kdr in \u003cem\u003eAnopheles subpictus\u003c/em\u003e was reported against organochlorine toxins in India, Pakistan, and Sri Lanka, but no resistance was observed in Mekong Delta. In this vector, the range of the kdr ratio was between 70 and 90%. Resistance to organochlorine pesticides was originally noted in India and then spread to Sri Lanka and Pakistan due to the L1014F mutation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Based on the findings, a lot of proportion of \u003cem\u003eAnopheles subpictus\u003c/em\u003e has resistance to organochlorine insecticides and this resistance has spread to other areas where this vector operates. Hence, it is necessary to use combined insecticides to fight this vector.\u003c/p\u003e","manuscriptTitle":"Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles subpictus): Systematic Reviews Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-08 04:27:21","doi":"10.21203/rs.3.rs-4358998/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa694c16-9c9f-4438-92ce-95368993f398","owner":[],"postedDate":"May 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-08T04:27:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-08 04:27:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4358998","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4358998","identity":"rs-4358998","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}