# The Perpetual Vector Mosquito Threat and Its Eco-Friendly Nemeses
## 3 Integrated Pest Management Programs (IPMPs) for Mosquito Control
### Synthetic Pesticides
Regarding the latter, it is well-established that insect cytochrome P450 monooxygenases, esterases, and glutathione S-transferases (GSTs) play significant roles in the detoxification of plant toxins and xenobiotic, such as natural and synthetic insecticides. Generally, (i) monooxygenases are involved in the metabolism of virtually all insecticides; (ii) esterases can metabolize organophosphates, carbamates, and pyrethroids, which are rich in ester bonds; and (iii) GSTs can neutralize the effect of pyrethroids, organochlorides, and organophosphates. Currently, factors leading to the hyperepression of genes coding for monooxygenases, esterases, and GSTs in response to synthetics in mosquitoes are of considerable interest [91; 92; 93; 94; 95]. Regarding the insecticide target site specificity, certain site-specific mutations in sodium channel proteins, acetylcholinesteraseases, and GABA receptors are strongly associated with resistance to their ligand pesticides. For example, studies by [PERSON] et al. [96] and [PERSON] et al. [97] on the sodium channel of _Culex quinquefasciatus_ showed that at least three specific nonsynonymous mutations (A109S, L982F, W1573R) were directly associated with resistance to permethrin, and that six synonymous mutations (codons for L582, G891, A241, P1249, and G1733) that do not alter the amino acid sequence may play a role in the evolution of resistance. In _Culex_ and _Anopheles_, in addition to other insect species that display an insensitivity or a reduced sensitivity to organophosphates and carbamates, a mutation in the _achel_ gene conferring a G119S substitution likely causes steric hindrance that reduces the accessibility of the inhibitor pesticide substrate to acetylcholine esterase 1 (AChE1) [83; 98; 99; 100; 101]. The major neuronal inhibitory mechanism in insects (and vertebrates) is the GABAergic system, in which activation suppresses neuronal excitability. The GABA receptor is targeted by dieldrin and fipronil, which are cyclodiene and phenyl pyrazole insecticides, respectively. Mutations resulting in A296S/G substitutions in the GABA receptor are associated with dieldrin resistance in many insects, including _Anopheles gambiae_ (A296G), _Anopheles arabiensis, Anopheles stephensi, Anopheles fintetus_, and _Aedes aegypti_ (A296S), and generally lower levels of resistance to fipronil [83; 102; 103; 104; 105; 106; 107]. In other regards, it is interesting to note that the GABAergic system also plays an important role in immune regulation in mammals, for example, in the autoimmune inflammation and migration of immune cells in response to parasitic infection with _Toxoplasma gondii_[108; 109; 110]. It is now apparent that a similar role for GABA signaling occurs in mosquitoes. [PERSON] et al. [111] showed that (i) the dsRNA-mediated disruption of GABA and the specific inhibition of GABA\({}_{\rm A}\) receptor decrease arboviral replication, whereas the introduction of glutamic acid per os increases the ability of arboviruses to infect mosquitoes; (ii) blood meals enhance viral replication through GABAergic activation; and (iii) the GABAergic system suppresses the Imd pathway, an NF-kB pathway known to regulate bacterial and malarial infection in mosquitoes [112; 113; 114]. Given this scenario, the extent to which sublethal levels of insecticides dampen or inhibit the GABAergic system, and how resistance to these synthetics influence the propagation of pathogens in natural mosquito populations, remain to be resolved. Nevertheless, [PERSON] et al. [111] demonstrated that at least two GABA inhibitors, fipronil and bilobalide, markedly reduced dengue (DENV-2) and Zika virus loads in _Aedes aegypti_ that survived treatment with these chemicals, a finding that suggests that inhibitors of the GABAergic system may play a role in reducing the dissemination of arboviruses in the field.