Insecticides Resistance And Underlying Biological Mechanisms Which Aggravate The Burden Of Malaria In Developing Countries
Despite considerable success of malaria control programme in the past, malaria still continues as a major public health problem. The malaria control relies mainly on indoor residual spraying of insecticides, which has become an inspiring fear task due to widespread resistance in malaria vectors, however, any disease control strategy should take into account insecticide-resistance management as it can greatly impact its success (vector control failures) and may have a direct effect on pathogen transmission. Current vector control strategies rely heavily on insecticide interventions. Unfortunately, the effectiveness of insecticide-based vector control is being threatened as mosquitoes develop resistance to the insecticides. Insecticide resistance has been recognized as one of most serious obstacles in global mosquito control. This review showed that how insecticides are involved to eliminate vector borne diseases. Therefore monitoring of insecticide resistance at regular intervals is necessary so that an effective management strategy can be designed.
Introduction
Malaria remains a major public health concern worldwide and has a profound socio-economic impact on countries where it is endemic. Globally, in 2015 an estimated 429, 000 deaths from malaria occurred most of which were in children aged under 5 years in Africa. Africa bears the greatest burden of malaria accounting for approximately 92% of malaria deaths. Malaria has been a leading cause of morbidity and mortality among people of the Dry Zone of Sri Lanka throughout its known history. Since October 2012, no cases of indigenous malaria have been reported in Sri Lanka. In 2016, Sri Lanka was certified by the WHO as a country which eliminated the malaria, as a life-threatening disease.
It is of vital importance, therefore, that research continues to understand the impact of the problem and find ways of managing this growth in insecticide resistance. For IRS, several strategies have been proposed which might prevent or slow down resistance. Vector control remains one of the central components for malaria control through larval source reduction and adult vector control.
Insecticides
Insecticide resistance in pest populations affects both economy and public health at a worldwide scale: it decreases crop yields (and thus profitability), induces the need to increase the quantity of insecticide and to develop new insecticides (thereby having a strong impact on costs and on the environment), and finally it is responsible for higher incidence of human or animal diseases. Resistance is defined as a heritable decrease of the susceptibility to an insecticide.
Three categories of resistance can be distinguished: behavioral (avoidance of contact with insecticide), physiological (e. g. , increased cuticle thickness), and biochemical (enhanced insecticide detoxification and sequestration and/or decreased insecticide target sensitivity). Few examples of behavioral (e. g. , Anopheles gambiae on Bioko Is- land and Senegal or Anopheles funestus in Benin and Tanzania and physiological resistances have been reported; whether they are heritable remains debated, and it is difficult to assess the level of protection they provide. Biochemical resistances typically result in relatively high level of protection and are genetically determined. Resistant individuals carry one or several genetic mutations that prevent insecticide disruption of the target functioning. As a result, the frequency of resistance gene(s)/allele(s) increases in the population over time. Insecticide resistance is confirmed by toxicological tests (bioassays) establishing resistance ratio (or RR corresponding to the number by which an insecticide dose must be multiplied in order to obtain the same mortality in resistant than in susceptible insects). It can be investigated at many levels, from the molecular characterization of genes/alleles conferring resistance and their biochemical products, to the effect of these genes on the fitness (i. e. , mean reproductive success) of the individuals carrying resistance alleles, to the dynamics and evolution of these resistance alleles in natural vector populations and their effect on disease control.
The first case of resistance was reported in 1908, in a population of San Jose scale (Aspidiotus perniciosus) resistant to lime sulfur. A century later (2007), 553 arthropod species were reported as resistant to at least one insecticide, among many disease vectors. More than 100 mosquito species are resistant to at least one insecticide (including 56 Anopheline species, 39 Culicine species); Culex pipiens pipiens and Anopheles albimanus are resistant to more than 30 different compounds.
Synthetic insecticides
Four major classes of organic (synthetic) insecticides are used to control insects: the organochlorines (OCs), the organophosphates (OPs), the carbamates (CXs), and the pyrethroids (PYRs), with, 4429, 1375, 30, and 414 metrictonnes respectively, of active ingredient used annually for global vector control from 2000 to 2009.
The use of synthetic insecticides was started back in 1943 for control of malaria. The first synthetic insecticide was Dichloro Diphenyl Trichloroethane (DDT) and later cyclodiene (CD) dieldrin was also started to use. From the late 1970s, OCs was replaced by the PYRs class of vector control, and these became widely used in malaria vector control. They are today by far the most-used insecticides, with 81% of the World spray coverage. PYR-based indoor residual spraying (IRS) and insecticide-treated nets and curtains (ITNs) are currently advocated as standard malaria vector control strategies. Finally, two other classes of synthetic insecticides are used at a large scale world- wide: the OPs and the CXs, which were first used in the 1940s and the 1950s, respectively.
They are usually used as larvicides (although some are now considered for ITN impregnation and IRS as an alternative to PYR, and are particularly well suited for species with delimited breeding sites. OCs and PYRs are highly popular due to their very low toxicity to human and long half-life in the environment, which makes it more cost effective in vector control. On the other hand OPs and CXs have a short half-life; and two to three rounds of IRS are needed per year. This significantly reduces the cost effectiveness of the use of these two classes of insecticides. However, when compared to OCs and PYRs these two groups evidently have less potential of developing resistance. Furthermore, the latter two groups have less environmental impacts due to its lower half-life in environment than OCs and PYRs. Some new groups of insecticides such as neonicotinoids, phthalic acid diamides, or anthranilic acid diamides were introduced in 2006-2008 period. However, these groups did not become much popular in disease vector control despite their popularity in agricultural pest control.
During the same period another group of synthetic insecticides were introduced. These interfere with insect physiological processes by mimicking certain compounds produced in endocrine system. Synthetic insect growth regulators (IGR) are one of the best examples for this. Furthermore synthetic products called juvenoids that mimic the juvenile hormone (JH) and chitine inhibitors are also some examples for this.
Mechanisms of resistance
The targets of most insecticides are critical proteins of the insect nervous system. Insecticides bind to specific sites on their targets and disrupt their function. Any mechanism that decreases the insecticide effect will lead to resistance. This encompasses reduced penetration of the insecticide, increased excretion or sequestration of the insecticide, increased metabolism of the insecticide, and finally target modification that limits the binding of the insecticide. The first three mechanisms are poorly documented and do not seem to play a prominent role in resistance.
Metabolic resistance includes the various mechanisms that lead to the degradation of the insecticide in less- or nontoxic products, thus decreasing the quantity of toxic molecules that reach the target. The detoxification through enzymatic reactions is one of the major ways of metabolic resistance. There are several groups of enzymes that involved in this type of resistance mechanisms. For an instance Glutathione S-Transferases (GSTs), carboxyl esterases (COEs) and cytochrome P450 monooxygenases (P450s) are three of the major groups [26]. Among these GSTs catalyze the reaction between sulfhydryl group and electrophilic sites of xenobiotics and form conjugates that are more readily excreted and typically less toxic than the parent insecticide and this group associated with resistance to OCs, particularly DDT, and OPs COEs on the other hand, act by binding to an ester group on the xenobiotic molecule and then break the ester bound by a process of acylation, de-acylation. The majority of insecticides, including almost all CXs and OPs, most PYRs, and some IGRs bear ester groups; hence resistance may develop due to the action of COEs. The other group, P450s involved in detoxification through monooxygenase activity and is responsible for the resistance to several groups of insecticides, particularly DDT, PYRs, and CXs.
Resistance by target-site modification is due to point mutations in the insecticide target gene that results in reduced binding of insecticides. For an instance resistance to CDs may develop due to a decreased sensitivity to insecticide of the GABA receptor A, through a point mutation causing an amino acid change in the receptor- coding gene. The extensive use of CDs before their banning in the 1980s resulted in a resistance in several insect species.
VGSCs are glycoproteins with a pore for ion transport and can adopt three different states: resting, open, or inactivated; the Na+ ions pass only when the channels are open.
VGSC are the targets of DDT and PYRs. When these insecticides bind to the VGSC, they slow their closing speed, prolonging the depolarization. One major mechanism, named knockdown resistance (kdr), is responsible for PYR and DDT resistance, by reducing the receptors sensitivity (binding capacity) to these insecticides and modifying the action potential of the channel.
AChE is the target of OPs and CXs insecticides, which are competitive inhibitors of AChE when they bind to AChE; their very slow release prevents hydrolysis of the natural substrate. Consequently, AChE remains active in the synaptic cleft and the nervous influx is continued, leading to insect death by tetany. In most insects there are two genes, ace-1 and ace-2, coding for AChE1 and AChE2, respectively. In these species, AChE1 is the main synaptic enzyme while the physiological role of AChE2 is still uncertain. Diptera of the Cyclorrapha group or “true” fiies (such as D. melanogaster and M. domestica) possess a single AChE, which is encoded by the ace-2 gene and is the synaptic enzyme in that case. In mosquitoes where AChE1 is the synaptic enzyme, the most common resistance mutation (G119S) in the ace-1 gene is located just near the active site.
Juvenoids mimic JH and disrupt insect development. Few resistance cases have been described in various species. High resistance to methoprene has been described in the mosquito Ochlerotatus nigromaculis in California, potentially through target-site mutation. While 7. 7-fold resistance to the same insecticide has been reported in C. p. pipiens from New York.
Bacillus thuringiensis (Bt) toxins have a complex mode of action not clearly understood. Bt resistance is increasing in the field in several pests. Presently, the only report of field resistance in mosquito is a 33-fold resistance to Bti (Bacillus thuringiensis var. israelensis) the only Bt variety active on mosquitoes) detected in a natural population of C. p. pipiens from New York. However, the mechanism of this resistance was not investigated. Genomic studies suggested several candidates for Bti resistance in Ae. Aegypti, but they are not yet validated finally; it appears that depending on the environmental conditions, some of the four Bti toxins may be inactivated, which could favor the emergence of full Bti resistance through intermediate bouts of selection to each toxin independently.
For Bacillus sphaericus (Bs) toxins, resistance has been described essentially in mosquitoes of the C. pipiens complex, due to mutation in the toxin receptor. It developed very rapidly within the first year of treatment in India and in Tunisia. Similarly, control using Bs toxins started in the early 1990s in Southern France and first failure was reported in 1994 in Port-Louis (near Marseille). This resistance was due to a recessive sex-linked gene, named sp-1. In 1996, Bs resistance was reported close to the Spain border it was due to a second gene, sp-2, which was recessive and sex-linked. Now Bs resistance has been observed worldwide in the C. pipiens complex. Two of the alleles identified (sp-2R and an allele selected in a laboratory strain from California change the toxin receptor binding properties, and were found to be due to “stop” mutations or mobile element insertion in the toxin receptor.
To control these diseases and upgrade the socioeconomic burden they cause in developing countries, vector control remains a powerful and accessible tool. However, any disease control strategy should take into account insecticide-resistance management as it can greatly impact its success (vector control failures) and may have a direct effect on pathogen transmission. This includes first establishing a continuous survey of resistance at a local scale by implicating the local population, a difficult but essential task to set goals and evaluate success. Several survey sites in different conditions are required for sentinel purposes, together with some baseline information, to rapidly detect resistance, identify the mechanisms, and change the policies adequately.
These local surveys should then be integrated at a more global scale for vector control coordination, allowing informed decisions for using alternative tools to insecticides and preserving the remaining insecticides by carefully planning their use to minimize resistance selection. Variation in insecticide resistance mainly depends upon the type of insecticide and frequency of use. Although various mechanisms of insecticide resistance in insects such as metabolic resistance (i. e. esterases, monooxygenase or glutathione-s- transferase), resistance due to reduced penetration or behavioral resistance are reported in several vectors, generally it is governed by either involvement of metabolic mechanisms or alterations at target sites. Revealing the mechanism of resistance is equally important to that of monitoring resistance in mosquito vectors. An Anopheles species are highly resistant to DDT. Insecticide resistance is a serious emerging problem in Developing countries. Currently, the national program has no alternative insecticide for effective vector control or for insecticide resistance management. There are some insecticides available for vector control, an approach focused on the rotational use of insecticides or a mosaic strategy can be adopted to delay development of resistance in malaria vectors. Also, highlighting needs to be given to other ecofriendly methods of vector control, such as bio control with larvivorous fish and biolarvicides especially Bacillus thuringiensis var. israelensis included in the integrated vector management program. Effective resistance management mainly depends upon early detection of the status of resistance, therefore monitoring of insecticide resistance at regular intervals is necessary so that an effective management strategy can be designed.
Target-site modification
Voltage-gated sodium channels (VGSCS)
Acetylcholinesterase (AChE)
Other resistance mechanismsgrowth regulators
Toxin receptors
Conclusion
