Adedeji et al. Parasites Vectors (2020) 13:465 https://doi.org/10.1186/s13071-020-04342-5 Parasites & Vectors REVIEW Open Access Anopheles metabolic proteins in malaria transmission, prevention and control: a review Eunice Oluwatobiloba Adedeji1,2, Olubanke Olujoke Ogunlana1,2, Segun Fatumo3, Thomas Beder4, Yvonne Ajamma1, Rainer Koenig4* and Ezekiel Adebiyi1,5,6* Abstract The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an efective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identifcation of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmis- sion exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specifcity can yield insecticides with no signifcant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will signifcantly help to curb malaria transmission. Keywords: Immune response, Insecticide, Insecticide resistance, Plasmodium, Vector control, Acetylcholinesterase Background another [2, 3]. Te major Anopheles species include An. Malaria remains a universal health challenge afect- gambiae, An. stephensi, An. dirus, An. coluzzii, An. albi- ing over 200 million of the world’s population annu- manus, An. funestus and An. arabiensis amongst others. ally. Although malaria burden is highest in Africa (93% Transmission of Plasmodium depends on the completion of malaria cases), a global incidence rate of 57 cases per of its developmental cycle in the mosquito, a process that 1000 population has been reported annually between occurs alongside the digestion of the blood meal and egg 2014–2018 [1]. Malaria is an infectious disease caused development in the mosquito [4]. Tis blood meal is cru- by the parasite Plasmodium and transmitted by female cial for oogenesis [5]. Hence, Anopheles mosquito’s ability Anopheles mosquitoes, which vary from one region to to transmit malaria is directly linked to its ability to feed on and digest a blood meal from a malaria-infected per- son [6]. Tese processes i.e. blood digestion, egg devel- *Correspondence: [email protected]; ezekiel. [email protected] opment and parasite development in the mosquito occur 1 Covenant University Bioinformatics Research (CUBRe), Covenant simultaneously and are tightly linked to metabolism. University, Ota, Ogun State, Nigeria Metabolism refers to all the enzyme-catalyzed chemi- 4 Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, cal transformations that occur in the cell of an organism Germany [7] and metabolic proteins consist of enzymes as well as Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Adedeji et al. Parasites Vectors (2020) 13:465 Page 2 of 30 transporters. Since metabolism is substantial for the sur- and control, a critical review of their roles can provide vival and proper functioning of an organism, metabolic insights into the possibilities of utilizing Anopheles meta- proteins provide a good biological space to serve as vec- bolic proteins for more targeted vector control strategies. tor control targets. Terefore, this review summarizes the information on Interestingly, some metabolic proteins involved in the role of Anopheles metabolic proteins in the transmis- digesting ingested blood, absorbing nutrients and oogen- sion and control of malaria as well as gives insights into esis, also play a role in the development of Plasmodium future targeted vector control strategies. Te role of met- in the mosquito [8]. For example, trypsin produced in abolic proteins is discussed under the following headings: Anopheles midgut might activate Plasmodium chitinase insecticide target; resistance to insecticides; blood diges- that allows the parasite to evade physical barriers in the tion; immune response; and Plasmodium development in mosquito [9]. In addition, ingestion of the parasite by the mosquito, and their manipulation for vector control Anopheles triggers an innate immune response in the strategies. mosquito to circumvent parasite development [10]. Tis immune response is a cascade of reactions involving some metabolic proteins of the mosquito. Tis interplay Metabolic proteins as insecticide targets suggests the importance of metabolic proteins in Plas- Insecticides are crucial for controlling the malaria vec- modium development in the mosquito and consequently tor and consequently, preventing malaria transmission. malaria transmission. Aside from being involved in blood Te four main classes of insecticides used for both indoor digestion and parasite development, Anopheles metabolic and outdoor spraying are organophosphates, organochlo- proteins such as the acetylcholinesterase (AChE) are, rides, carbamates and pyrethroids. Pyrethroids are used also important targets for vector control strategies [11]. in ITNs because of their insecticidal potency and relative Figure 1 gives a schematic overview of the contributions safety for domestic use [24]. Many of the known insec- of the metabolic proteins of Anopheles mosquitoes in ticides act on proteins that mediate neuronal processes. malaria transmission and control. Examples of these insecticide targets are AChE, gamma- In the past decades, vector control greatly depended on aminobutyric acid (GABA)-chloride ionophore com- the use of insecticides for indoor residual spraying (IRS) plexes, sodium ion channels [25–27]. However, out of the and insecticide-treated nets (ITNs) [12]. Tese strategies four classes of insecticides employed for malaria control greatly reduced malaria deaths between 2010 and 2015, program, only carbamates and organophosphates target a as 50% reduction in malaria deaths was reported and 79% metabolic protein. of this reduction was attributed to insecticide use [13]. Organophosphate and carbamate insecticides com- Some insecticides target metabolic proteins. For instance, petitively inhibit AChE (EC 3.1.1.7), an enzyme that AChE has been the only target of organophosphate and hydrolyzes acetylcholine into acetate and choline [25, carbamate insecticides for many years [14]. In addition, 28]. Tis hydrolysis reaction terminates the transmis- AChE is the target for temephos and fenthion that are sion of the cholinergic neuronal signal after an excitation organophosphate insecticides and target the larval stage signal [29]. Inhibition of this reaction results in continu- of mosquitoes, and thus, are used in larviciding strategies ous stimulation of the nervous system and consequently [15]. Tese larvicides, upon application to breeding sites leads to the death of the mosquito [30]. Tese insecti- of mosquitoes, prevent their further development into cides elicit their inhibitory efects by forming a covalent adult forms, consequently, reducing adult mosquito pop- bond with the catalytic serine residue of AChE [25]. Most ulation density and ultimately decreasing malaria trans- insects, including Anopheles, have two AChE genes, ace1 mission rates [16]. Meanwhile, the toxicity of many of the (AChE1) and ace2 (AChE2) [31, 32]. However, AChE1 currently available insecticides to non-target species and is the major nervous system cholinesterase in many of the ever increasing resistance of Anopheles to commonly these insects and experimental evidence exists showing used classes of insecticides,