Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles albimanus, Anopheles darlingi, Anopheles dirus and Anopheles punctipennis): A Systematic Review Study

Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles albimanus, Anopheles darlingi, Anopheles dirus and Anopheles punctipennis): A Systematic Review 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 albimanus, Anopheles darlingi, Anopheles dirus and Anopheles punctipennis): A Systematic Review Study Ebrahim Abbasi, Salman Daliri This is a preprint; it has not been peer reviewed by a journal.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-5012727/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Nov, 2025 Read the published version in Malaria Journal → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Anopheles albimanus , Anopheles darlingi , Anopheles dirus , and Anopheles punctipennis are malaria vectors in many world regions. The resistance of these vectors against insecticides, especially organochlorine insecticides, has significantly hindered efforts to control them. Although one of the causes of resistance is kdr mutation, studies in this field have been done sporadically. As a result, this study was conducted to investigate the kdr mutation in the mentioned vectors using a systematic review method. Methods This study was conducted as a systematic review of kdr mutation in Anopheles albimanus , Anopheles darlingi , Anopheles dirus , and Anopheles punctipennis . Therefore, the international scientific databases PubMed, Web of Science, Cochrane Library, Scopus, Science Direct, and Google Scholar were searched, and all relevant articles were extracted and surveyed without a time limit until the end of June 2024. The quality assessment of the articles was done using the Strobe checklist. Result Five articles were included in the systematic review process. The findings indicated that kdr mutation was not observed in any of the four species of Anopheles albimanus , Anopheles darlingi , Anopheles dirus , and Anopheles punctipennis , and the causes of resistance are other factors, including other metabolic resistances such as MFO and NSE. Conclusion Based on the findings, kdr mutation does not play any role in creating resistance in Anopheles albimanus , Anopheles darlingi , Anopheles dirus , and Anopheles punctipennis . Considering these vectors' various behavioral and biological characteristics, other metabolic and behavioral can cause resistance against organochlorine insecticides. Consequently, there is a need to conduct studies on the factors that cause resistance in these vectors. Anopheles albimanus Anopheles darlingi Anopheles dirus Anopheles punctipennis Knockdown resistance Organochlorine insecticide Figures Figure 1 Introduction Anopheles is the primary vector of malaria in the world and has more than 400 species, 40 of which are known as malaria vectors. Anopheles albimanus is one of the main malaria vectors in the Caribbean islands, Central America, and the northern regions of South America ( 1 ). An. albimanus is zoophilic, exophagic, and corpuscular and has higher compatibility than other anopheline species ( 2 ). This species has a flexible behavior that can affect its spread in lower and more temperate latitudes ( 3 ). Various insecticides, such as organochlorine, organophosphorus, and pyrethroids, have been used to control this vector. However, in recent decades, this vector's resistance against the insecticides DDT, lambda-cyhalothrin, deltamethrin, and malathion has been widely reported ( 4 – 6 ). Various factors have been mentioned as the causes of resistance in this vector, but the most important of them is metabolic resistance, especially knockdown resistance (kdr), which has been considered in the field of resistance to organochlorine insecticides. Although studies have mentioned various results in this field, further investigation is required ( 7 ). Anopheles darling is one of the main vectors of malaria, and as the dominant species in the Neotropical region, it leads to malaria transmission ( 8 ). This vector is widely present in South and Central America, Panama, Mexico, Argentina, and the Atlantic coast ( 8 , 9 ). The population of Anopheles darlingi increased due to deforestation and human settlements ( 10 , 11 ). This species is the focal vector of malaria in South and Central America, causing an increase in malaria in this region ( 12 , 13 ). Due to its endophilic properties, this transporter is controlled by the IRS. After the use of DDT to fight Anopheles was suspended, organochlorine, organophosphorus, and pyrethroids, including lambda-cyhalothrin and deltamethrin, are used to fight this vector ( 14 ). However, recently, the resistance of this vector against insecticides has increased and even led to cross-resistance between insecticides. The existence of cross-resistance among different insecticides, which can be caused by mutations in target sites and metabolic mechanisms, is a serious obstacle to its use in malaria control programs ( 15 ). Anopheles dirus is another malaria vector in Southeast Asia and is common in Thailand, Myanmar, Indochina, and China ( 16 – 18 ). It has seven different types; the most common types are A, B, C, and D. These species have high biological, behavioral, and biological diversity and remarkable ability to adapt to the environment ( 16 , 19 , 20 ). This vector is prevalent in dense forest areas and is one of the leading causes of falciparum malaria in this region. Behavioral change and their ability to adapt to the environment have increased the resistance of this vector against various types of insecticides ( 21 ). The development of resistance in Anopheles mosquitoes has made it very difficult to control these vectors. Mechanisms of resistance to insecticides in Anopheles include metabolic resistance, resistance at the target site, cuticular resistance, and behavioral resistance, of which resistance at the target site and metabolic resistance play a significant role in creating resistance to insecticides ( 22 ). Resistance at the target site, with a change in the amino acid sequence of the voltage-gated sodium channel, leads to a decrease in the sensitivity of mosquitoes to pyrethroid and organochlorine insecticides and is known as kdr ( 23 , 24 ). The widespread distribution of insecticide resistance, especially organochlorine insecticides worldwide, has affected the epidemiology of malaria. Therefore, raising awareness about the impact of insecticides and the potential for resistance is crucial for understanding and managing malaria transmission. Accordingly, monitoring the resistance of malaria vectors against insecticides to implement control programs is essential to verify the effectiveness of control tools. Thus, this study was conducted to investigate the presence of kdr mutation in causing resistance to organochlorine insecticides in An. albimanus , An. darlingi , and An. dirus worldwide using a systematic review method. Materials and Methods Study protocol This study is a systematic review in the field of kdr mutation in An. albimanus, An. darlingi, An. dirus , and An. punctipennis based on PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) ( 25 ). Also, this study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the code CRD42021231605. Search strategy Articles were extracted without a time limit until the end of June 2024 from PubMed, Web of Science, Cochrane Library, Scopus, Science Direct, and Google Scholar databases and keywords of resistance, knockdown mutations, knockdown resistance, kdr, insecticide resistance, organochlorine insecticide, organochlorine, insecticide, dichloroethane, DDT, aldrin, lindane, dieldrin, malaria vectors, Anopheles, An. albimanus, An. darlingi, An. dirus , and An. punctipennis were searched in the title, abstract and keywords in singular and compound form using AND and OR operators. Inclusion and exclusion criteria All the English-language articles published worldwide that were conducted on malaria vectors, including An. albimanus, An. darlingi, An. dirus , An. punctipennis , and kdr resistance and mutation were investigated, and resistance to organochlorine insecticides was evaluated in them. High-quality articles were included in the study. Articles that did not meet the inclusion criteria investigated other insecticides, or were conducted using case reports or case series were excluded from the study. Quality assessment The quality assessment of the articles was done based on 22 parts of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist, examining compliance with the principles of writing and implementation in the title, method of reporting findings, limitations, and conclusions. Each item on the checklist is assigned a score based on importance, with a maximum possible score of 33 ( 26 ). Screening and data extraction At first, considering the inclusion and exclusion criteria, the title and abstract of the articles were examined independently by two researchers. Two researchers then reviewed the full text of the articles. If an article was rejected, the reason was documented. In cases of disagreement between the two researchers, a third reviewer evaluated the article. Data extraction was done using a previously prepared checklist, including study location, study time, insecticide type, vector type, and kdr mutation. Study selection Results Globally, about 40 species of Anopheles mosquitoes carry malaria. Understanding their biological and behavioral characteristics, as well as effective control methods, is essential for combating and reducing malaria. However, insecticide resistance poses a significant obstacle to controlling these vectors. Organochlorine insecticides have been used to control these vectors for a long time, but resistance, especially of the kdr type, has limited the use of these insecticides. Four species of An. albimanus, An. darlingi, An. dirus , and An. punctipennis , have caused the spread of malaria in different regions worldwide. The cause of resistance in these vectors has not been widely investigated in the world, and it is unclear whether kdr mutation is the cause of resistance in these vectors. In the following section, kdr mutation was investigated in the mentioned transporters. Kdr in Anopheles albimanus An. albimanus is one of the main malaria vectors in various world regions ( 3 ). In the past, resistance to organochlorine insecticides, which are widely used to deal with this vector, has been reported. Studies of metabolic mechanisms or insensitivity of the target site, such as mutations in the sodium channel gene (VGSC), have mentioned the cause of this resistance ( 27 , 28 ). It has been shown that increasing the activity level of esterases and oxidases plays an important role in creating resistance in this vector ( 29 ). High oxidase activity and a target site mechanism have also been implicated in cross-resistance between DDT and pyrethroids in An. albimanus ( 30 ). Considering the research done on kdr mutation in An. albimanus , only one study has been conducted in Colombia by Orjuela et al. (2019). in which sequencing of all the samples in the forward and reverse direction has been done in the context of three codons of 1010, 1013, and 1014, which are related to resistance to organochlorine insecticides and pyrethroids in malaria vectors. The findings identified the GTT codon at position 1010 (V1010), AAC codon (for asparagine) at position 1013 (N1013), and TTA and TTG codons (for leucine) at position 1014, revealing that no amino acid mutation was observed in the sequences and there is no kdr mutation in them ( 31 ). Even though this study has shown that the kdr mutation plays a role in An. Albimanus resistance, it is not resistant to organochlorine insecticides, and more studies are required to confirm this claim. Kdr in Anopheles darlingi An. darlingi is one of the vectors of malaria in the world, and it can be found especially in the Amazon region and Africa. This vector has a wide global occurrence and differentiation in genetic, morphological, and behavioral traits, leading to the creation and spread of various insecticide resistance mechanisms ( 32 , 33 ). For many years, neurotoxic insecticides have been used to deal with this vector. To deal with this vector, it is necessary to evaluate its sensitivity; however, the resistance or sensitivity of this vector has rarely been evaluated so far. Organochlorine insecticides, especially DDT, cause paralysis or death of this transporter by targeting the voltage-gated sodium channel ( 27 , 34 ). However, kdr mutation has recently been considered. In the study of Orjuela et al. (2019) in Colombia done on An. darlingi , knockdown mutations did not create resistance to organoleptic insecticides. In this study, all samples were analyzed in the forward and reverse direction of sequencing, and three codons, 1010, 1013, and 1014, are related to resistance to organochlorine insecticides and pyrethroids in malaria vectors. The findings identified the GTT codon at position 1010 (V1010), AAC codon (for asparagine) at position 1013 (N1013), and TTA and TTG codons (for leucine) at position 1014, indicating that no amino acid mutation was observed in the sequences and there is no kdr in them ( 31 ). Fonseca-González et al. (2009) in Colombia investigated kdr in An. darlingi against organochlorine insecticides and pyrethroids. The findings showed that all populations of An. darlingi were sensitive to deltamethrin, permethrin, and malathion. Resistance to lambda-cyhalothrin and DDT was observed in the population, demonstrating 65 to 75% mortality. Cross-resistance between these two insecticides was also observed. However, specific resistance due to kdr was not observed, and the cause of resistance was reported to be increased metabolism through MFO and NSE ( 6 ). Based on the investigated studies, it can be mentioned that kdr mutation has not been observed in An. darlingi , and the cause of resistance in this vector can be metabolic mechanisms and increased activity of oxidases and esterases. Kdr in Anopheles dirus An. dirus complex is one of the malaria vectors that can be found in Asia, especially its forest areas. This species has biological and ecological differences and behavioral changes when it is in contact with humans and exposed to environmental stimuli which can improve carrying capacity and environmental adaptation ( 16 , 35 , 36 ). These changes can increase resistance to control measures in this vector. Organochlorine insecticides have been one of the main insecticides used to combat this vector since a long time ago, and the main cause of resistance to these insecticides was reported to be kdr mutation ( 37 ). Verhaeghen et al. (2009) investigated kdr in 73 An. dirus mosquitoes in Vietnam. Based on their study, sequencing was performed in the DIIS6 region of the para-type sodium channel gene for the samples to identify kdr, but the results did not show any kdr mutations among the samples ( 38 ). Sumarnrote et al. (2017) investigated the kdr mutation in An. dirus against the insecticide deltamethrin in Vietnam. The results of the genetic sequencing of the samples did not show any L1014F or L1014S substitutions in the VGSC gene. Additionally, the attenuation ratio of this transporter against deltamethrin was 100%, which indicates that it is sensitive to this insecticide ( 39 ). In the study by Zeng et al. (2017) in Hainan Province, the attenuation ratio of An. dirus against the insecticides deltamethrin (0.05%), DDT (4%), malathion (5%), and cyfluthrin (0.15%) was 100%, revealing the high sensitivity of this vector against organochlorine insecticides. It should also be mentioned that no kdr mutation was observed in this study ( 21 ). In general, kdr mutation has not been detected to create resistance in this vector, and this vector has a high sensitivity to insecticides, including organochlorines. Kdr in Anopheles Punctipennis An. punctipennis is a common and widespread malaria vector in the United States and North America ( 3 ). This vector can transmit Plasmodium vivax and Plasmodium falciparum [9]. It can also transmit Plasmodium odocoilei to wild animals such as deer, which increases their biodiversity and makes fighting it more complex ( 40 , 41 ). Also, creating resistance to insecticides in this vector can be another limitation of controlling it. While searching, only one study was found which investigated the kdr mutation in this vector. Orjuela et al. (2019) investigated the kdr mutation in An. punctipennis . The results of sequencing the samples identified the GTT codon at position 1010 (V1010), AAC codon at position 1013 (N1013), and TTA and TTG codons at position 1014. which shows that no amino acid and kdr mutations were observed in the sequences ( 31 ). Although this study has shown no kdr mutation in this vector, more studies are needed to confirm this issue. Discussion In this study, kdr resistance in An. Albimanus was investigated, and the findings showed no kdr resistance mutation in this vector. There are various mechanisms for Anopheles’ insecticide resistance, including behavioral, cuticular, metabolic, and target site resistance, in which metabolic resistance and resistance to the target site play a greater role in creating resistance to insecticides ( 42 ). In the studies that were conducted, it was mentioned that metabolic resistance creates resistance in An. Albimanus. In sodium channel 9, natural mutations at positions N1013 (S), V1010 (L), I1048 (N), L1014 (F/S/C/W), N1575 (Y) and S1156 (G) are found to be associated with the phenotype resistance in Anopheles ( 6 , 43 ). Besides, only mutations identified at position 1014 are involved in reducing sodium channel sensitivity to insecticides ( 7 , 44 ). An. Albimanus mutations at positions L1014F and L1014C can lead to kdr, which has not been identified in the studies carried out so far ( 30 ). However, it should also be noted that only a small region of the VGSC gene is often evaluated in sequencing. As a result, there is a possibility that mutations and resistance created by mutations occurring in different regions of the gene can be communicated, so it is recommended to examine a longer region of the gene ( 7 ). In general, the studies reporting kdr mutation's role in creating resistance in An. Albimanus have not been provided. However, confirmation of this issue requires conducting more studies in this field. In the present systematic review, kdr resistance in An. darlingi and An. dirus was not reported. Other studies have shown that in the populations of An. darlingi and An. dirus , metabolic mechanisms have played an essential role in resistance, and the level of functional oxidases has increased in resistant Anopheles ( 6 ). Additionally, in pyrethroid-resistant Anopheles, an increase in the levels of non-specific esterases has been reported ( 43 ). In vectors resistant to organochlorine insecticides and pyrethroids, metabolic detoxification and reduction of cuticular penetration have also been observed ( 45 – 49 ). These cases can generally cause high resistance levels without kdr mutations ( 50 ). Other studies investigating the resistance of Anopheles An. darlingi has reported high levels of AChE against organophosphates and carbamates ( 29 ). In a study conducted in Mexico, an increase in the level of cytochrome P450 and the activity of glutathione S-transferase and esterase was observed in DDT-resistant Anopheles ( 29 ). Studies have shown that in the population of An. darlingi , resistance to carbamates and organophosphates is associated with mutations in ace-1, resistance to pyrethroids is associated with mutations in the VGSC gene, and resistance to deltamethrin and alpha-cypermethrin is associated with cytochrome P450 CYP9K1 and overexpression of CYP6P5 ( 30 , 51 , 52 ). Considering the presence of kdr mutations in most DDT-resistant Anopheles species in different regions of the world, the absence of this mutation in the mentioned vectors can reflect genetic limitations or reduce insecticide pressure ( 51 , 53 ). Also, the activity of An. dirus is strongly related to the foothills, deep forests, and forest margins, which can affect its behavioral characteristics and reduce the effect of insecticides on them ( 16 ). Since no kdr mutation was observed in the mentioned vectors, metabolic and behavioral resistance mechanisms can play a major role in developing resistance. Hence, we can mention different factors and mechanisms that create resistance in An. darlingi and An. dirus . Overall, the studies have not implicated the kdr mechanism in developing resistance. However, studies in this field are few, and more studies are needed. Conclusion Based on the findings, kdr mutation does not play any role in creating resistance in An. albimanus , An. darlingi, An. dirus , and An. punctipennis . Considering these vectors various behavioral and biological characteristics, other metabolic and behavioral causes can play a role in creating resistance against organochlorine insecticides. Besides, limited studies have been done to investigate the resistance of kdr in these transporters; as a result, it is necessary to conduct more studies on the activity of these transporters in the field of resistance-causing factors. Declarations Ethics approval and consent to participate Not applicable. Availability of data and materials All data obtained from this study are included in the text of article. Competing interests The authors declare no competing interests . 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. EA wrote the article. All authors read and approved the final manuscript. 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Pyrethroid and organophosphates resistance in Anopheles (N.) nuneztovari Gabaldón populations from malaria endemic areas in Colombia. Parasitology research. 2009;105:1399-409. Orjuela LI, Morales JA, Ahumada ML, Rios JF, González JJ, Yañez J, et al. Insecticide resistance and its intensity in populations of malaria vectors in Colombia. BioMed Research International. 2018;2018(1):9163543. Rakotondranaivo T, Randriamanarivo SF, Tanjona MR, Vigan-Womas I, Randrianarivelojosia M, Ndiath MO. Evidence of insecticide resistance to pyrethroids and bendiocarb in Anopheles funestus from Tsararano, Marovoay District, Madagascar. BioMed Research International. 2018;2018(1):5806179. Tchigossou G, Djouaka R, Akoton R, Riveron JM, Irving H, Atoyebi S, et al. Molecular basis of permethrin and DDT resistance in an Anopheles funestus population from Benin. Parasites & vectors. 2018;11:1-13. Matowo J, Kulkarni MA, Mosha FW, Oxborough RM, Kitau JA, Tenu F, et al. Biochemical basis of permethrin resistance in Anopheles arabiensis from Lower Moshi, north-eastern Tanzania. Malaria journal. 2010;9:1-9. Balabanidou V, Kampouraki A, MacLean M, Blomquist GJ, Tittiger C, Juárez MP, et al. Cytochrome P450 associated with insecticide resistance catalyzes cuticular hydrocarbon production in Anopheles gambiae. Proceedings of the National Academy of Sciences. 2016;113(33):9268-73. Bonizzoni M, Afrane Y, Dunn WA, Atieli FK, Zhou G, Zhong D, et al. Comparative transcriptome analyses of deltamethrin-resistant and-susceptible Anopheles gambiae mosquitoes from Kenya by RNA-Seq. 2012. Yahouédo GA, Chandre F, Rossignol M, Ginibre C, Balabanidou V, Mendez NGA, et al. Contributions of cuticle permeability and enzyme detoxification to pyrethroid resistance in the major malaria vector Anopheles gambiae. Scientific reports. 2017;7(1):11091. Liebman KA, Pinto J, Valle J, Palomino M, Vizcaino L, Brogdon W, et al. Novel mutations on the ace-1 gene of the malaria vector Anopheles albimanus provide evidence for balancing selection in an area of high insecticide resistance in Peru. Malaria journal. 2015;14:1-10. Mackenzie-Impoinvil L, Weedall GD, Lol JC, Pinto J, Vizcaino L, Dzuris N, et al. Contrasting patterns of gene expression indicate differing pyrethroid resistance mechanisms across the range of the New World malaria vector Anopheles albimanus. PLoS One. 2019;14(1):e0210586. Karunaratne 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. Table 1 Table 1. Characteristics of the articles included in the systematic review Author Year Study Place Study Sample Size Type of Anopheles Orjuela L (31) 2019 Colombia 126 An. albimanus, An. Darling and An. Punctipennis Fonseca-González I (6) 2009 Colombia 120 An. darlingi Verhaeghen K (38) 2009 Mekong region 60 An. dirus Sumarnrote A (39) 2017 Thailand 34 An. dirus Zeng LH (21) 2011 China 90 An. dirus Additional Declarations No competing interests reported. Supplementary Files PRISMA2020checklistandSearchstrategysyntax.docx Cite Share Download PDF Status: Published Journal Publication published 19 Nov, 2025 Read the published version in Malaria Journal → Version 1 posted Editorial decision: Revision requested 21 May, 2025 Reviews received at journal 19 May, 2025 Reviews received at journal 23 Oct, 2024 Reviewers agreed at journal 02 Oct, 2024 Reviewers agreed at journal 02 Oct, 2024 Reviewers invited by journal 11 Sep, 2024 Editor assigned by journal 02 Sep, 2024 Submission checks completed at journal 02 Sep, 2024 First submitted to journal 01 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-5012727","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":361514279,"identity":"8831a03a-86b4-46bf-8ab4-25552b05cc03","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":361514280,"identity":"4f664c90-a6b2-45ca-b4f6-030ebcb01ecd","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":"2024-09-01 11:51:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5012727/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5012727/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12936-025-05659-1","type":"published","date":"2025-11-19T15:56:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66310399,"identity":"969e316b-80e9-40f7-9bcc-4c2ce2a771b4","added_by":"auto","created_at":"2024-10-10 08:34:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1586467,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram\u003c/p\u003e\n\u003cp\u003eThe review process based on the PRISMA flow diagram\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5012727/v1/6405f08e906fc597dc0febb5.png"},{"id":96651051,"identity":"7dc516d0-45f2-4f2e-b93d-da7849be820e","added_by":"auto","created_at":"2025-11-24 16:13:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2519074,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5012727/v1/968b488c-17d5-4685-891a-73366251f956.pdf"},{"id":66311274,"identity":"161c690d-4c48-426a-bdcc-75194acf53b2","added_by":"auto","created_at":"2024-10-10 08:42:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":113317,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklistandSearchstrategysyntax.docx","url":"https://assets-eu.researchsquare.com/files/rs-5012727/v1/c057bc72a1dccdfc5a06691d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles albimanus, Anopheles darlingi, Anopheles dirus and Anopheles punctipennis): A Systematic Review Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnopheles is the primary vector of malaria in the world and has more than 400 species, 40 of which are known as malaria vectors. \u003cem\u003eAnopheles albimanus\u003c/em\u003e is one of the main malaria vectors in the Caribbean islands, Central America, and the northern regions of South America (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). \u003cem\u003eAn. albimanus\u003c/em\u003e is zoophilic, exophagic, and corpuscular and has higher compatibility than other anopheline species (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). This species has a flexible behavior that can affect its spread in lower and more temperate latitudes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Various insecticides, such as organochlorine, organophosphorus, and pyrethroids, have been used to control this vector. However, in recent decades, this vector's resistance against the insecticides DDT, lambda-cyhalothrin, deltamethrin, and malathion has been widely reported (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Various factors have been mentioned as the causes of resistance in this vector, but the most important of them is metabolic resistance, especially knockdown resistance (kdr), which has been considered in the field of resistance to organochlorine insecticides. Although studies have mentioned various results in this field, further investigation is required (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnopheles darling is one of the main vectors of malaria, and as the dominant species in the Neotropical region, it leads to malaria transmission (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This vector is widely present in South and Central America, Panama, Mexico, Argentina, and the Atlantic coast (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The population of \u003cem\u003eAnopheles darlingi\u003c/em\u003e increased due to deforestation and human settlements (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). This species is the focal vector of malaria in South and Central America, causing an increase in malaria in this region (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Due to its endophilic properties, this transporter is controlled by the IRS. After the use of DDT to fight Anopheles was suspended, organochlorine, organophosphorus, and pyrethroids, including lambda-cyhalothrin and deltamethrin, are used to fight this vector (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, recently, the resistance of this vector against insecticides has increased and even led to cross-resistance between insecticides. The existence of cross-resistance among different insecticides, which can be caused by mutations in target sites and metabolic mechanisms, is a serious obstacle to its use in malaria control programs (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eAnopheles dirus\u003c/em\u003e is another malaria vector in Southeast Asia and is common in Thailand, Myanmar, Indochina, and China (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). It has seven different types; the most common types are A, B, C, and D. These species have high biological, behavioral, and biological diversity and remarkable ability to adapt to the environment (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This vector is prevalent in dense forest areas and is one of the leading causes of falciparum malaria in this region. Behavioral change and their ability to adapt to the environment have increased the resistance of this vector against various types of insecticides (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe development of resistance in Anopheles mosquitoes has made it very difficult to control these vectors. Mechanisms of resistance to insecticides in Anopheles include metabolic resistance, resistance at the target site, cuticular resistance, and behavioral resistance, of which resistance at the target site and metabolic resistance play a significant role in creating resistance to insecticides (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Resistance at the target site, with a change in the amino acid sequence of the voltage-gated sodium channel, leads to a decrease in the sensitivity of mosquitoes to pyrethroid and organochlorine insecticides and is known as kdr (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The widespread distribution of insecticide resistance, especially organochlorine insecticides worldwide, has affected the epidemiology of malaria. Therefore, raising awareness about the impact of insecticides and the potential for resistance is crucial for understanding and managing malaria transmission. Accordingly, monitoring the resistance of malaria vectors against insecticides to implement control programs is essential to verify the effectiveness of control tools. Thus, this study was conducted to investigate the presence of kdr mutation in causing resistance to organochlorine insecticides in \u003cem\u003eAn. albimanus\u003c/em\u003e, \u003cem\u003eAn. darlingi\u003c/em\u003e, and \u003cem\u003eAn. dirus\u003c/em\u003e worldwide using a systematic review method.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy protocol\u003c/h2\u003e \u003cp\u003eThis study is a systematic review in the field of kdr mutation in \u003cem\u003eAn. albimanus, An. darlingi, An. dirus\u003c/em\u003e, and \u003cem\u003eAn. punctipennis\u003c/em\u003e based on PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Also, this study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the code CRD42021231605.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eArticles were extracted without a time limit until the end of June 2024 from PubMed, Web of Science, Cochrane Library, Scopus, Science Direct, and Google Scholar databases and keywords of resistance, knockdown mutations, knockdown resistance, kdr, insecticide resistance, organochlorine insecticide, organochlorine, insecticide, dichloroethane, DDT, aldrin, lindane, dieldrin, malaria vectors, Anopheles, \u003cem\u003eAn. albimanus, An. darlingi, An. dirus\u003c/em\u003e, and \u003cem\u003eAn. punctipennis\u003c/em\u003e were searched in the title, abstract and keywords in singular and compound form using AND and OR operators.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eAll the English-language articles published worldwide that were conducted on malaria vectors, including \u003cem\u003eAn. albimanus, An. darlingi, An. dirus\u003c/em\u003e, \u003cem\u003eAn. punctipennis\u003c/em\u003e, and kdr resistance and mutation were investigated, and resistance to organochlorine insecticides was evaluated in them. High-quality articles were included in the study. Articles that did not meet the inclusion criteria investigated other insecticides, or were conducted using case reports or case series were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003eThe quality assessment of the articles was done based on 22 parts of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist, examining compliance with the principles of writing and implementation in the title, method of reporting findings, limitations, and conclusions. Each item on the checklist is assigned a score based on importance, with a maximum possible score of 33 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eScreening and data extraction\u003c/h2\u003e \u003cp\u003eAt first, considering the inclusion and exclusion criteria, the title and abstract of the articles were examined independently by two researchers. Two researchers then reviewed the full text of the articles. If an article was rejected, the reason was documented. In cases of disagreement between the two researchers, a third reviewer evaluated the article. Data extraction was done using a previously prepared checklist, including study location, study time, insecticide type, vector type, and kdr mutation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eGlobally, about 40 species of Anopheles mosquitoes carry malaria. Understanding their biological and behavioral characteristics, as well as effective control methods, is essential for combating and reducing malaria. However, insecticide resistance poses a significant obstacle to controlling these vectors. Organochlorine insecticides have been used to control these vectors for a long time, but resistance, especially of the kdr type, has limited the use of these insecticides.\u003c/p\u003e \u003cp\u003eFour species of \u003cem\u003eAn. albimanus, An. darlingi, An. dirus\u003c/em\u003e, and \u003cem\u003eAn. punctipennis\u003c/em\u003e, have caused the spread of malaria in different regions worldwide. The cause of resistance in these vectors has not been widely investigated in the world, and it is unclear whether kdr mutation is the cause of resistance in these vectors. In the following section, kdr mutation was investigated in the mentioned transporters.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKdr in\u003c/b\u003e \u003cb\u003eAnopheles albimanus\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eAn. albimanus\u003c/em\u003e is one of the main malaria vectors in various world regions (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In the past, resistance to organochlorine insecticides, which are widely used to deal with this vector, has been reported. Studies of metabolic mechanisms or insensitivity of the target site, such as mutations in the sodium channel gene (VGSC), have mentioned the cause of this resistance (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). It has been shown that increasing the activity level of esterases and oxidases plays an important role in creating resistance in this vector (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). High oxidase activity and a target site mechanism have also been implicated in cross-resistance between DDT and pyrethroids in \u003cem\u003eAn. albimanus\u003c/em\u003e (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Considering the research done on kdr mutation in \u003cem\u003eAn. albimanus\u003c/em\u003e, only one study has been conducted in Colombia by Orjuela et al. (2019). in which sequencing of all the samples in the forward and reverse direction has been done in the context of three codons of 1010, 1013, and 1014, which are related to resistance to organochlorine insecticides and pyrethroids in malaria vectors. The findings identified the GTT codon at position 1010 (V1010), AAC codon (for asparagine) at position 1013 (N1013), and TTA and TTG codons (for leucine) at position 1014, revealing that no amino acid mutation was observed in the sequences and there is no kdr mutation in them (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Even though this study has shown that the kdr mutation plays a role in An. Albimanus resistance, it is not resistant to organochlorine insecticides, and more studies are required to confirm this claim.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKdr in\u003c/b\u003e \u003cb\u003eAnopheles darlingi\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eAn. darlingi\u003c/em\u003e is one of the vectors of malaria in the world, and it can be found especially in the Amazon region and Africa. This vector has a wide global occurrence and differentiation in genetic, morphological, and behavioral traits, leading to the creation and spread of various insecticide resistance mechanisms (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). For many years, neurotoxic insecticides have been used to deal with this vector. To deal with this vector, it is necessary to evaluate its sensitivity; however, the resistance or sensitivity of this vector has rarely been evaluated so far. Organochlorine insecticides, especially DDT, cause paralysis or death of this transporter by targeting the voltage-gated sodium channel (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). However, kdr mutation has recently been considered. In the study of Orjuela et al. (2019) in Colombia done on \u003cem\u003eAn. darlingi\u003c/em\u003e, knockdown mutations did not create resistance to organoleptic insecticides. In this study, all samples were analyzed in the forward and reverse direction of sequencing, and three codons, 1010, 1013, and 1014, are related to resistance to organochlorine insecticides and pyrethroids in malaria vectors. The findings identified the GTT codon at position 1010 (V1010), AAC codon (for asparagine) at position 1013 (N1013), and TTA and TTG codons (for leucine) at position 1014, indicating that no amino acid mutation was observed in the sequences and there is no kdr in them (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Fonseca-Gonz\u0026aacute;lez et al. (2009) in Colombia investigated kdr in \u003cem\u003eAn. darlingi\u003c/em\u003e against organochlorine insecticides and pyrethroids. The findings showed that all populations of \u003cem\u003eAn. darlingi\u003c/em\u003e were sensitive to deltamethrin, permethrin, and malathion. Resistance to lambda-cyhalothrin and DDT was observed in the population, demonstrating 65 to 75% mortality. Cross-resistance between these two insecticides was also observed. However, specific resistance due to kdr was not observed, and the cause of resistance was reported to be increased metabolism through MFO and NSE (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Based on the investigated studies, it can be mentioned that kdr mutation has not been observed in \u003cem\u003eAn. darlingi\u003c/em\u003e, and the cause of resistance in this vector can be metabolic mechanisms and increased activity of oxidases and esterases.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKdr in\u003c/b\u003e \u003cb\u003eAnopheles dirus\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eAn. dirus\u003c/em\u003e complex is one of the malaria vectors that can be found in Asia, especially its forest areas. This species has biological and ecological differences and behavioral changes when it is in contact with humans and exposed to environmental stimuli which can improve carrying capacity and environmental adaptation (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). These changes can increase resistance to control measures in this vector. Organochlorine insecticides have been one of the main insecticides used to combat this vector since a long time ago, and the main cause of resistance to these insecticides was reported to be kdr mutation (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Verhaeghen et al. (2009) investigated kdr in 73 \u003cem\u003eAn. dirus\u003c/em\u003e mosquitoes in Vietnam. Based on their study, sequencing was performed in the DIIS6 region of the para-type sodium channel gene for the samples to identify kdr, but the results did not show any kdr mutations among the samples (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Sumarnrote et al. (2017) investigated the kdr mutation in \u003cem\u003eAn. dirus\u003c/em\u003e against the insecticide deltamethrin in Vietnam. The results of the genetic sequencing of the samples did not show any L1014F or L1014S substitutions in the VGSC gene.\u003c/p\u003e \u003cp\u003eAdditionally, the attenuation ratio of this transporter against deltamethrin was 100%, which indicates that it is sensitive to this insecticide (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). In the study by Zeng et al. (2017) in Hainan Province, the attenuation ratio of \u003cem\u003eAn. dirus\u003c/em\u003e against the insecticides deltamethrin (0.05%), DDT (4%), malathion (5%), and cyfluthrin (0.15%) was 100%, revealing the high sensitivity of this vector against organochlorine insecticides. It should also be mentioned that no kdr mutation was observed in this study (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In general, kdr mutation has not been detected to create resistance in this vector, and this vector has a high sensitivity to insecticides, including organochlorines.\u003c/p\u003e \u003cp\u003e \u003cb\u003eKdr in\u003c/b\u003e \u003cb\u003eAnopheles Punctipennis\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cem\u003eAn. punctipennis\u003c/em\u003e is a common and widespread malaria vector in the United States and North America (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This vector can transmit Plasmodium vivax and Plasmodium falciparum [9]. It can also transmit \u003cem\u003ePlasmodium odocoilei\u003c/em\u003e to wild animals such as deer, which increases their biodiversity and makes fighting it more complex (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Also, creating resistance to insecticides in this vector can be another limitation of controlling it. While searching, only one study was found which investigated the kdr mutation in this vector. Orjuela et al. (2019) investigated the kdr mutation in \u003cem\u003eAn. punctipennis\u003c/em\u003e. The results of sequencing the samples identified the GTT codon at position 1010 (V1010), AAC codon at position 1013 (N1013), and TTA and TTG codons at position 1014. which shows that no amino acid and kdr mutations were observed in the sequences (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Although this study has shown no kdr mutation in this vector, more studies are needed to confirm this issue.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, kdr resistance in An. Albimanus was investigated, and the findings showed no kdr resistance mutation in this vector. There are various mechanisms for Anopheles\u0026rsquo; insecticide resistance, including behavioral, cuticular, metabolic, and target site resistance, in which metabolic resistance and resistance to the target site play a greater role in creating resistance to insecticides (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). In the studies that were conducted, it was mentioned that metabolic resistance creates resistance in An. Albimanus. In sodium channel 9, natural mutations at positions N1013 (S), V1010 (L), I1048 (N), L1014 (F/S/C/W), N1575 (Y) and S1156 (G) are found to be associated with the phenotype resistance in Anopheles (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Besides, only mutations identified at position 1014 are involved in reducing sodium channel sensitivity to insecticides (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). An. Albimanus mutations at positions L1014F and L1014C can lead to kdr, which has not been identified in the studies carried out so far (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). However, it should also be noted that only a small region of the VGSC gene is often evaluated in sequencing. As a result, there is a possibility that mutations and resistance created by mutations occurring in different regions of the gene can be communicated, so it is recommended to examine a longer region of the gene (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In general, the studies reporting kdr mutation's role in creating resistance in An. Albimanus have not been provided. However, confirmation of this issue requires conducting more studies in this field.\u003c/p\u003e \u003cp\u003eIn the present systematic review, kdr resistance in \u003cem\u003eAn. darlingi\u003c/em\u003e and \u003cem\u003eAn. dirus\u003c/em\u003e was not reported. Other studies have shown that in the populations of \u003cem\u003eAn. darlingi\u003c/em\u003e and \u003cem\u003eAn. dirus\u003c/em\u003e, metabolic mechanisms have played an essential role in resistance, and the level of functional oxidases has increased in resistant Anopheles (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Additionally, in pyrethroid-resistant Anopheles, an increase in the levels of non-specific esterases has been reported (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). In vectors resistant to organochlorine insecticides and pyrethroids, metabolic detoxification and reduction of cuticular penetration have also been observed (\u003cspan additionalcitationids=\"CR46 CR47 CR48\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). These cases can generally cause high resistance levels without kdr mutations (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). Other studies investigating the resistance of Anopheles \u003cem\u003eAn. darlingi\u003c/em\u003e has reported high levels of AChE against organophosphates and carbamates (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In a study conducted in Mexico, an increase in the level of cytochrome P450 and the activity of glutathione S-transferase and esterase was observed in DDT-resistant Anopheles (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Studies have shown that in the population of \u003cem\u003eAn. darlingi\u003c/em\u003e, resistance to carbamates and organophosphates is associated with mutations in ace-1, resistance to pyrethroids is associated with mutations in the VGSC gene, and resistance to deltamethrin and alpha-cypermethrin is associated with cytochrome P450 CYP9K1 and overexpression of CYP6P5 (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering the presence of kdr mutations in most DDT-resistant Anopheles species in different regions of the world, the absence of this mutation in the mentioned vectors can reflect genetic limitations or reduce insecticide pressure (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). Also, the activity of \u003cem\u003eAn. dirus\u003c/em\u003e is strongly related to the foothills, deep forests, and forest margins, which can affect its behavioral characteristics and reduce the effect of insecticides on them (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Since no kdr mutation was observed in the mentioned vectors, metabolic and behavioral resistance mechanisms can play a major role in developing resistance. Hence, we can mention different factors and mechanisms that create resistance in \u003cem\u003eAn. darlingi\u003c/em\u003e and \u003cem\u003eAn. dirus\u003c/em\u003e. Overall, the studies have not implicated the kdr mechanism in developing resistance. However, studies in this field are few, and more studies are needed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on the findings, kdr mutation does not play any role in creating resistance in \u003cem\u003eAn. albimanus\u003c/em\u003e, \u003cem\u003eAn. darlingi, An. dirus\u003c/em\u003e, and \u003cem\u003eAn. punctipennis\u003c/em\u003e. Considering these vectors various behavioral and biological characteristics, other metabolic and behavioral causes can play a role in creating resistance against organochlorine insecticides. Besides, limited studies have been done to investigate the resistance of kdr in these transporters; as a result, it is necessary to conduct more studies on the activity of these transporters in the field of resistance-causing factors.\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\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data obtained from this study are included in the text of article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\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\u003c/p\u003e\n\u003cp\u003eEA 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. EA wrote the article. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the Research Vice-chancellor of Shiraz University of Medical Sciences.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSinka ME, Bangs MJ, Manguin S, Rubio-Palis Y, Chareonviriyaphap T, Coetzee M, et al. A global map of dominant malaria vectors. Parasites \u0026amp; vectors. 2012;5:1-11.\u003c/li\u003e\n\u003cli\u003eV\u0026aacute;zquez-Mart\u0026iacute;nez MG, Rodr\u0026iacute;guez MH, Arredondo-Jim\u0026eacute;nez JI, M\u0026eacute;ndez-S\u0026aacute;nchez JD, Bond-Compe\u0026aacute;n JG, Gold-Morgan M. Cyanobacteria associated with Anopheles albimanus (Diptera: Culicidae) larval habitats in southern Mexico. 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Malaria journal. 2015;14:1-11.\u003c/li\u003e\n\u003cli\u003eLol JC, Casta\u0026ntilde;eda D, Mackenzie-Impoinvil L, Romero CG, Lenhart A, Padilla NR. Development of molecular assays to detect target-site mechanisms associated with insecticide resistance in malaria vectors from Latin America. Malaria journal. 2019;18:1-9.\u003c/li\u003e\n\u003cli\u003eCorbel V, Nosten F, Thanispong K, Luxemburger C, Kongmee M, Chareonviriyaphap T. Challenges and prospects for dengue and malaria control in Thailand, Southeast Asia. Trends in parasitology. 2013;29(12):623-33.\u003c/li\u003e\n\u003cli\u003eSukkanon C, Nararak J, Bangs MJ, Hii J, Chareonviriyaphap T. Behavioral responses to transfluthrin by Aedes aegypti, Anopheles minimus, Anopheles harrisoni, and Anopheles dirus (Diptera: Culicidae). PLoS One. 2020;15(8):e0237353.\u003c/li\u003e\n\u003cli\u003eNkya TE, Akhouayri I, Kisinza W, David J-P. Impact of environment on mosquito response to pyrethroid insecticides: facts, evidences and prospects. Insect biochemistry and molecular biology. 2013;43(4):407-16.\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\u003eSumarnrote A, Overgaard HJ, Marasri N, Fustec B, Thanispong K, Chareonviriyaphap T, et al. Status of insecticide resistance in Anopheles mosquitoes in Ubon Ratchathani province, Northeastern Thailand. Malaria journal. 2017;16:1-13.\u003c/li\u003e\n\u003cli\u003eMartinsen ES, McInerney N, Brightman H, Ferebee K, Walsh T, McShea WJ, et al. Hidden in plain sight: Cryptic and endemic malaria parasites in North American white-tailed deer (Odocoileus virginianus). Science Advances. 2016;2(2):e1501486.\u003c/li\u003e\n\u003cli\u003eGuggisberg AM, Sayler KA, Wisely SM, Odom John AR. Natural history of Plasmodium odocoilei malaria infection in farmed white-tailed deer. Msphere. 2018;3(2):10.1128/msphere. 00067-18.\u003c/li\u003e\n\u003cli\u003eSuh PF, Elanga-Ndille E, Tchouakui M, Sandeu MM, Tagne D, Wondji C, et al. Impact of insecticide resistance on malaria vector competence: a literature review. Malaria Journal. 2023;22(1):19.\u003c/li\u003e\n\u003cli\u003eFonseca-Gonz\u0026aacute;lez I, C\u0026aacute;rdenas R, Qui\u0026ntilde;ones ML, McAllister J, Brogdon WG. Pyrethroid and organophosphates resistance in Anopheles (N.) nuneztovari Gabald\u0026oacute;n populations from malaria endemic areas in Colombia. Parasitology research. 2009;105:1399-409.\u003c/li\u003e\n\u003cli\u003eOrjuela LI, Morales JA, Ahumada ML, Rios JF, Gonz\u0026aacute;lez JJ, Ya\u0026ntilde;ez J, et al. Insecticide resistance and its intensity in populations of malaria vectors in Colombia. BioMed Research International. 2018;2018(1):9163543.\u003c/li\u003e\n\u003cli\u003eRakotondranaivo T, Randriamanarivo SF, Tanjona MR, Vigan-Womas I, Randrianarivelojosia M, Ndiath MO. Evidence of insecticide resistance to pyrethroids and bendiocarb in Anopheles funestus from Tsararano, Marovoay District, Madagascar. BioMed Research International. 2018;2018(1):5806179.\u003c/li\u003e\n\u003cli\u003eTchigossou G, Djouaka R, Akoton R, Riveron JM, Irving H, Atoyebi S, et al. Molecular basis of permethrin and DDT resistance in an Anopheles funestus population from Benin. Parasites \u0026amp; vectors. 2018;11:1-13.\u003c/li\u003e\n\u003cli\u003eMatowo J, Kulkarni MA, Mosha FW, Oxborough RM, Kitau JA, Tenu F, et al. Biochemical basis of permethrin resistance in Anopheles arabiensis from Lower Moshi, north-eastern Tanzania. Malaria journal. 2010;9:1-9.\u003c/li\u003e\n\u003cli\u003eBalabanidou V, Kampouraki A, MacLean M, Blomquist GJ, Tittiger C, Ju\u0026aacute;rez MP, et al. Cytochrome P450 associated with insecticide resistance catalyzes cuticular hydrocarbon production in Anopheles gambiae. Proceedings of the National Academy of Sciences. 2016;113(33):9268-73.\u003c/li\u003e\n\u003cli\u003eBonizzoni M, Afrane Y, Dunn WA, Atieli FK, Zhou G, Zhong D, et al. Comparative transcriptome analyses of deltamethrin-resistant and-susceptible Anopheles gambiae mosquitoes from Kenya by RNA-Seq. 2012.\u003c/li\u003e\n\u003cli\u003eYahou\u0026eacute;do GA, Chandre F, Rossignol M, Ginibre C, Balabanidou V, Mendez NGA, et al. Contributions of cuticle permeability and enzyme detoxification to pyrethroid resistance in the major malaria vector Anopheles gambiae. Scientific reports. 2017;7(1):11091.\u003c/li\u003e\n\u003cli\u003eLiebman KA, Pinto J, Valle J, Palomino M, Vizcaino L, Brogdon W, et al. Novel mutations on the ace-1 gene of the malaria vector Anopheles albimanus provide evidence for balancing selection in an area of high insecticide resistance in Peru. Malaria journal. 2015;14:1-10.\u003c/li\u003e\n\u003cli\u003eMackenzie-Impoinvil L, Weedall GD, Lol JC, Pinto J, Vizcaino L, Dzuris N, et al. Contrasting patterns of gene expression indicate differing pyrethroid resistance mechanisms across the range of the New World malaria vector Anopheles albimanus. PLoS One. 2019;14(1):e0210586.\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\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Characteristics of the articles included in the systematic review\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear Study\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlace Study\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eAnopheles\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003eOrjuela L\u0026nbsp;\u003cstrong\u003e(31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003eColombia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003ealbimanus,\u0026nbsp;\u003c/em\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003eDarling\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eand\u003cem\u003e\u0026nbsp;An.\u0026nbsp;Punctipennis\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003eFonseca-Gonz\u0026aacute;lez I\u0026nbsp;\u003cstrong\u003e(6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003eColombia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003edarlingi\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003eVerhaeghen K\u0026nbsp;\u003cstrong\u003e(38)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003eMekong region\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003edirus\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003eSumarnrote A\u0026nbsp;\u003cstrong\u003e(39)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003eThailand\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003edirus\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.3943%;\"\u003e\n \u003cp\u003eZeng LH\u0026nbsp;\u003cstrong\u003e(21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9842%;\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.4038%;\"\u003e\n \u003cp\u003eChina\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.8265%;\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28.3912%;\"\u003e\n \u003cp\u003e\u003cem\u003eAn.\u0026nbsp;\u003c/em\u003e\u003cem\u003edirus\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anopheles albimanus, Anopheles darlingi, Anopheles dirus, Anopheles punctipennis, Knockdown resistance, Organochlorine insecticide","lastPublishedDoi":"10.21203/rs.3.rs-5012727/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5012727/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003e \u003cem\u003eAnopheles albimanus\u003c/em\u003e, \u003cem\u003eAnopheles darlingi\u003c/em\u003e, \u003cem\u003eAnopheles dirus\u003c/em\u003e, and \u003cem\u003eAnopheles punctipennis\u003c/em\u003e are malaria vectors in many world regions. The resistance of these vectors against insecticides, especially organochlorine insecticides, has significantly hindered efforts to control them. Although one of the causes of resistance is kdr mutation, studies in this field have been done sporadically. As a result, this study was conducted to investigate the kdr mutation in the mentioned vectors using a systematic review method.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study was conducted as a systematic review of kdr mutation in \u003cem\u003eAnopheles albimanus\u003c/em\u003e, \u003cem\u003eAnopheles darlingi\u003c/em\u003e, \u003cem\u003eAnopheles dirus\u003c/em\u003e, and \u003cem\u003eAnopheles punctipennis\u003c/em\u003e. Therefore, the international scientific databases PubMed, Web of Science, Cochrane Library, Scopus, Science Direct, and Google Scholar were searched, and all relevant articles were extracted and surveyed without a time limit until the end of June 2024. The quality assessment of the articles was done using the Strobe checklist.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eFive articles were included in the systematic review process. The findings indicated that kdr mutation was not observed in any of the four species of \u003cem\u003eAnopheles albimanus\u003c/em\u003e, \u003cem\u003eAnopheles darlingi\u003c/em\u003e, \u003cem\u003eAnopheles dirus\u003c/em\u003e, and \u003cem\u003eAnopheles punctipennis\u003c/em\u003e, and the causes of resistance are other factors, including other metabolic resistances such as MFO and NSE.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBased on the findings, kdr mutation does not play any role in creating resistance in \u003cem\u003eAnopheles albimanus\u003c/em\u003e, \u003cem\u003eAnopheles darlingi\u003c/em\u003e, \u003cem\u003eAnopheles dirus\u003c/em\u003e, and \u003cem\u003eAnopheles punctipennis\u003c/em\u003e. Considering these vectors' various behavioral and biological characteristics, other metabolic and behavioral can cause resistance against organochlorine insecticides. Consequently, there is a need to conduct studies on the factors that cause resistance in these vectors.\u003c/p\u003e","manuscriptTitle":"Knockdown Resistance (kdr) Associated Organochlorine Resistance in Mosquito-Borne Diseases (Anopheles albimanus, Anopheles darlingi, Anopheles dirus and Anopheles punctipennis): A Systematic Review Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-10 08:34:04","doi":"10.21203/rs.3.rs-5012727/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-21T12:34:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-19T14:15:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-23T22:21:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32115567974027311613712997239888919572","date":"2024-10-02T12:57:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51687795468074575007210057381270062162","date":"2024-10-02T12:23:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-11T12:17:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-02T16:09:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-02T16:08:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Malaria Journal","date":"2024-09-01T11:48:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"malaria-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"malj","sideBox":"Learn more about [Malaria Journal](http://malariajournal.biomedcentral.com/)","snPcode":"12936","submissionUrl":"https://submission.nature.com/new-submission/12936/3","title":"Malaria Journal","twitterHandle":"@malariajournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa694c16-9c9f-4438-92ce-95368993f398","owner":[],"postedDate":"October 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:10:47+00:00","versionOfRecord":{"articleIdentity":"rs-5012727","link":"https://doi.org/10.1186/s12936-025-05659-1","journal":{"identity":"malaria-journal","isVorOnly":false,"title":"Malaria Journal"},"publishedOn":"2025-11-19 15:56:53","publishedOnDateReadable":"November 19th, 2025"},"versionCreatedAt":"2024-10-10 08:34:04","video":"","vorDoi":"10.1186/s12936-025-05659-1","vorDoiUrl":"https://doi.org/10.1186/s12936-025-05659-1","workflowStages":[]},"version":"v1","identity":"rs-5012727","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5012727","identity":"rs-5012727","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}