Mosquitoes are one of the most dangerous insects in the world for humanity. Over one million people worldwide die from mosquito-borne diseases every year. Mosquito vectored diseases include protozoan diseases, i.e., malaria, filarial diseases such as dog heartworm, and viral diseases such as dengue, encephalitis, and yellow fever. In addition, mosquitoes transmit several diseases and parasites that dogs and horses are very susceptible too. These include dog heartworm, West Nile virus (WNV), and eastern equine encephalitis (EEE). Since its discovery, chemical insecticides have represented the most widely method used to control mosquito-borne vectors. However, the effects of chemical insecticides on mosquito vector populations are usually transitory because vectors can rapidly develop resistance against them. Each insecticide triggers the selection of one or more mechanisms of resistance. These mechanisms include changes in the target site of action and metabolic detoxification among others.
Mosquito-borne vectors are responsible for the transmission of various causative agents of infectious diseases that can be lethal for humans. During the last decades, several diseases have increased incidence and expanded into new geographical areas. Among the factors that can favor the spread of disease are the increase of population density, the increase of international travel, and the increase of the import and export of goods at international level . The number of recent notifications of mosquito-borne diseases in the world is a matter of concern, and currently there are no effective vaccines available against most of these diseases. In many parts of the world, mosquito presence is a problem because each season presents different species that are vectors of diseases with medical and animal importance because they feed from man and other organisms. Therefore, the only way to avoid epidemics of mosquito-borne diseases is through the control of insect vectors and through knowledge of its biology, behavior, and environmental factors that facilitate its transmission .
Mosquitoes’ vector characteristics vary depending on the particular conditions of their habitat of origin. During its life cycle, mosquito goes through four stages, which are egg, larva, pup, and adult, of which the first three stages need stagnant water to develop. Generally, adult mosquitoes are small insects, fragile, with slender bodies, a pair of narrow wings and three pairs of long slender legs. They vary in length from 3.16 to 1.2 inch (5 to 13 mm). They are equipped with an elongated proboscis with mouthparts adapted for piercing skin, which the female uses for snacks and to feed on blood.
Over the last decades, the struggle of pests has been based on the large-scale use of chemical pesticides, as well as the elimination of all containers, artificial or natural, which can be given favorable conditions for the development of the prolific mosquito breeding sites . However, the negative effects of chemicals on nontarget organism populations and the resistance development to these chemicals in mosquitoes, along with the resent resurgence of different diseases transmitted by mosquitoes, have led to search other alternative methods, more simple and sustainable for mosquito control.
2. Mosquito-borne diseases
With the recent expansion of
Mosquito-borne diseases occur when the specific biological agent that causes the disease is transmitted to human hosts through a nonhuman carrier called vector. Therefore, the chain of transmission involves three factors: one host, usually a human, an invertebrate vector responsible for spreading the disease, and the biological agent that may be a virus, bacterium, or parasite. Vectors may act biologically or mechanically, where the mechanical vectors only transport the pathogenic agent; however, in biological vectors, agent develops and multiplies before becoming infective to the vertebrate host . In that context, mosquito-borne diseases of public health importance are complex, and its occurrence will depend on the interaction of various factors such as biological, ecological, social, and economic factors .
Malaria or paludism is caused by parasites of genus
While the disease appeared to be under control in the 1950s, the infection again reappeared in many countries due to the resistance generated by vectors to insecticides of plasmodia and chloroquine. This disease is responsible for the deaths of between 700,000 and 2.7 million people . Moreover, malaria causes between 400 and 900 million cases of acute fever per year in children fewer than five years in these areas. Therefore, malaria is the disease with the highest prevalence in areas with limited economic resources, causing the largest number of cases in the warm and rainy seasons. The solution to eradicate this disease would be the application of vaccine .
2.2. Yellow fever
This disease is caused by the yellow fever virus, an arbovirus, belonging to the
Dengue is a viral disease caused by infection of four viruses, known as dengue 1, 2, 3, and 4, which is endemic in more than 100 countries in Africa, America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific, the latter two being the most severely affected. These viruses belong to the genus
This disease is of major interest to public health because of its great impact on morbidity and mortality in the world since it is the viral disease transmitted by mosquito vectors most common and important worldwide . The World Health Organization estimated that there may be 50 to 100 million dengue infections, a half-million hospitalizations, and 22,000 deaths worldwide every year . Moreover, because of the absence of a vaccine to protect the population at risk, vector control is the most important method for the prevention and interruption of the transmission of the disease. The use of chemical insecticides is a key component in the control of larvae and adult mosquito vector populations. However, derived from overuse for over five decades of these insecticides to interrupt the transmission of the virus, it has generated resistance to different molecules of insecticides by part of mosquito vectors .
2.4. Venezuelan equine encephalitis
This disease is caused by the Venezuelan equine encephalitis virus (VEE) or encephalomyelitis in horses, donkeys, zebras, and humans. VEE virus cause acute infections in vertebrates characterized by the presence of high viremia and disease development with varying degrees of severity. Once the equines get the disease, they may die suddenly or present progressive disorders of the central nervous system. Furthermore, in humans, it causes mild to severe influenza-like symptoms, with fever and headache. Around 4–14% of cases develop neurological complications and near 1% of reported cases die .
The VEE complex contains a number of virus, belonging to the
Epizootic and enzootic strains of VEE virus spread from northern Argentina to Florida and parts of the Rocky Mountains, being more frequent in northern South America. Since 1930, there have been 21 outbreaks of VEE throughout the American continent, being considered an emerging disease naturally due to mutations of the enzootic and endemic virus strains that circulate as a vector-borne disease among mammals host populations, especially in habitats such as forests and wetlands . Some of the strategies used to reduce outbreaks of VEE in horses are through the implementation of the TC-83 vaccine and by protecting against mosquitoes by wearing protective clothing and/or insecticides. Although, the TC-83 vaccine is used in laboratories, there is still no licensed vaccine available to humans for the prevention of infection by the epizootic strains of VEE virus .
2.5. Japanese encephalitis
Japanese encephalitis (JE) is a viral disease transmitted to humans by mosquitoes of the
JE is distributed across several areas of temperate and tropical Asia, with a higher incidence in rural areas of Southeast Asia, the Indian subcontinent and parts of Northern Asia. It also occurs, but less frequently in Japan, Taiwan, Singapore, Hong Kong, eastern Russia, and Australia . Although the virus affects all age-groups, regions where there have been widespread childhood vaccination campaigns against the disease, the age distribution has changed, increasing the proportion of cases in older children and adults . Therefore, the best alternative for control of JE it is the application of the vaccine, which is associated with the generation of neutralizing antibodies.
2.6. Lymphatic filariasis
Lymphatic filariasis, also know elephantiasis, is a parasitic disease caused by nematodes of the
2.7. Rift Valley fever
The disease is caused by the Rift Valley fever virus, an RNA virus belonging to the
2.8. West Nile fever
West Nile fever (WNF) is transmitted to humans through the bite of
2.9. Chikungunya fever
Chikungunya fever is a viral disease, manifested by fever and severe arthralgia, prevalent in Africa, Asia, and Europe, and now emerging and little studied in the Americas and the Caribbean Islands since 2013 . Chikungunya virus is transmitted to humans by
The Chikungunya virus is an enveloped positive-strand RNA virus, belonging to the
2.10. St. Louis encephalitis
St. Louis encephalitis (SLE) is a viral disease transmitted by mosquitoes of the
2.11. Eastern equine encephalitis
Eastern equine encephalitis (EEE) is caused by the eastern equine encephalitis virus (EEEV), an RNA virus classified in the family Togaviridae. EEE infections are characterized by symptoms such as fever, headache, nausea and vomiting, malaise and weakness, confusion, myalgia, arthralgia, and neck stiffness. The main vector species involved in outbreaks of disease are
2.12. Western equine encephalitis
The causal agent of Western equine encephalitis (WEE) is the WEE virus (WEEV), which is an arbovirus of the Togaviridae family, transmitted by mosquitoes of the
2.13. La Crosse encephalitis
La Crosse encephalitis (LAC) is a disease caused by the La Crosse encephalitis virus (LACV). LACV is spread through the bite of infected mosquitoes of the
2.14. Zika fever
Zika fever (ZIKF) is caused by Zika virus (ZIKV), a flavivirus belonging to the family Flaviviridae. It is a disease of monkeys and humans spread through the bite of infected
3. Mosquito control
The prevention and control of mosquito-borne diseases globally is conducted through a comprehensive and thorough method of pest management. Where programs are not intended to completely eliminate mosquito populations but rather are aimed to reduce their number and therefore minimize the risk of disease transmission. Methods used to mosquito control include the elimination of breeding sites and the control of mosquito larvae and adults. Larvicides, by applying chemical insecticides in the breeding sites, are the best strategy to kill larvae and pupae of mosquitoes in the water. Larvicides are present in several forms ranging from powder, tablets, or liquids and include methoprene, monomolecular surface films, larvicidal oils, chemical insecticides, neurotoxic insecticides, plant-derived products, and larvicidal bacteria . Adulticides technique is usually less efficient for mosquito control. However, it is the only way to kill adult mosquitoes and is the last line of defense in reducing mosquito populations. Some of the adulticide used for mosquito control include products derived from microorganisms, plants or minerals, synthetic molecules, organophosphates, some natural pyrethrins, or synthetic pyrethroids .
3.1. Chemical insecticides
Since its discovery, chemical insecticides have represented the most widely method used to control mosquito-borne vectors. However, the effects of chemical insecticides on mosquito vector populations are usually transitory because vectors can rapidly develop resistance against them. On the other hand, the environmental problems caused by the excessive use of chemical insecticides are a matter of current concern because it is estimated that about 2.5 million tons of pesticides are used annually, generating worldwide damage amounting to $100 billion annually . Some of the disadvantages that generates when using only chemical products are (a) the selection of new insecticide resistance in pest populations; (b) the resurgence of already treated populations; (c) the generation of waste, risks, and legal complications; (d) the destruction of beneficial species; and (e) the high costs in equipment, labor, and material. In addition, the highly toxic and nonbiodegradable properties of insecticides and waste generated in soil, water, food, and crops that affect public health are additional reasons to search new methods to help solve the problems caused by chemical insecticides . Consequently, the concept of integrated control arises, a method in which pest and diseases control is performed using chemicals, useful organisms, and cultural practices.
The progress of science and the chemical industry in the nineteenth century, with the discovery of DDT, made possible the development and emergence of new conventional insecticides or so-called of synthesis . The most used of these insecticides of synthesis are modulators of sodium channels (organochlorines, pyrethroids, and pyrethrins), acetylcholinesterase inhibitors (carbamates and organophosphates), and the chloride channel antagonists regulated by the gamma-aminobutyric acid or also known as GABA (organochlorine cyclodiene and phenylpyrazoles).
Using these conventional insecticides gave positive results against insects disease vectors at first. However, due to its massive use, insects soon began to develop resistance to them. Thus, an insecticide that initially was effective, just being useless in the long term. In response to this problem, new-generation insecticides also called biorational insecticides have been developed, whose research strategy is based on a good understanding of the physiological processes or mechanisms specific communication of insects, and in obtaining agents that are able to affect them. These products are divided into the following: those who are analogs of juvenile hormone and molting, inhibitors tissue formation, pheromones, insecticides that prevent hatching, and biological insecticides .
3.1.1. Organophosphates and carbamates
Organophosphate insecticides are phosphoric acid derivatives, having activity against a wide spectrum of invertebrate. It interferes with the action of enzymes called cholinesterases that regulate the neurotransmitter acetylcholine, resulting in first instance to muscle cramps, paralysis, and eventually death . Therefore, these insecticides have a toxic action that blocks an enzyme acetylcholinesterase of central and peripheral nervous system of insects, in synaptic junctions. The enzyme rapidly hydrolyzed acetylcholine, resulting in the repolarization of the membrane or the basal plate in neuromuscular connections, preparing for the arrival of a new impulse. By forming strong covalent bonds between insecticide and acetylcholinesterase, the enzyme is inhibited, causing the accumulation of acetylcholine in the synaptic junction and the interruption of normal transmission of nerve impulses .
However, due to the generation of resistance in vector insects to these chemical products, the use of many of these organophosphate and carbamates insecticides is no longer effective. Furthermore, because cholinesterases and neurotransmitters acetylcholine also form part of vertebrate nervous system, organophosphate pesticides are highly or moderately toxic to vertebrates . In this regard, temephos are the only organophosphate pesticide that is still used to control mosquito larvae. Although temephos are not persistent in the environment being that last 7–10 days , it has been shown in many studies the adverse effects of temephos on a wide range of no target aquatic taxa . Furthermore, carbamate pesticides, just like organophosphates, act by inhibiting the cholinesterase enzyme. Therefore, the symptoms experienced by insects per carbamate poisoning are similar to those experienced with organophosphates. However, carbamate pesticides block acetylcholinesterase enzyme hydrolyzing acetylcholine in muscle by carbamylation, which is a reversible reaction . Therefore, the recovery of carbamate poisoning in humans is faster than with organophosphate intoxication since the acetylcholinesterase enzyme is able to break apart of the carbamate .
3.1.2. Organochlorines, pyrethroids, and pyrethrins
Organochlorine insecticides are chlorinated hydrocarbons, which are known to be effective to control mosquito populations. Its mode of action is by inhibiting GABA receptor in the nervous system through the interruption of nerve impulses due to the closure of chloride channels . Therefore, when an organochlorine binds to a GABA receptor, the receptor is unable to close GABA chloride channel, which results in stimulation of the nervous system and similar symptoms to poisoning with carbamates or organophosphates . However, with the Stockholm Convention on Persistent Organic Pollutants, which entered into force on May 17, 2004, the use of 12 chemicals including DDT, aldrin, dieldrin, heptachlor, mirex, chlordecone, and chlordane was prohibited because of its long average life and toxicity . However, an extension clause allows countries where malaria is endemic to use DDT to control vectors that transmit the disease. Taking into account the negative effects that DDT has for the environment, malaria programs without the use of insecticides have been developed with the assistance of the Pan American Health Organization .
On the other hand, pyrethroids and pyrethrins used to control mosquitoes break down faster in the sunlight as opposed to chemical or microbial breakdown. However, pyrethroids are considered axonic poisons, composed of more stable substances, or degrade slower in the presence of sunlight than pyrethrins and are generally effective against most of the insect pests of agriculture. Furthermore, pyrethroids can be combined with other active ingredients, such as piperonyl butoxide, to retard its degradation and prevents the insect’s system from detoxifying the pyrethroid, making it more effective . Delay that allows the chemical product persists longer in the environment, requiring smaller and less frequent doses to kill pests . This type of insecticidal affects the central and peripheral nervous system of insects and have a rapid knock-down effect, by interfering with the sodium channels of nerve membrane causing the interruption of the transfer of ions and transmission of impulses between nerve cells . Moreover, it stimulates nerve cells to produce repetitive discharges and eventually cause paralysis and death . Furthermore, because pyrethroids act on the nervous system of insects through a different pathway from the organophosphate pesticides, they generally have low toxicity in mammals and birds; however, they are toxic to fish and tadpoles .
3.1.3. Biorational insecticides
Biorational insecticides are those that have relatively low toxicity to humans and have few environmental effects. Among which, methoprene is an insect growth regulator insecticide with a broad spectrum of action that interferes with the insect life cycle preventing maturity or reproductive stage . Meanwhile, the juvenile hormone analogue is a biorational insecticide that causes deformations in larval stage, death in the pupal stage, and sterility effect in adults . Spinosad is another biorational insecticide that comes from a
3.2. Plants and their derivates
For centuries, nature has created several active substances that, when applied correctly, can control insect pests such as mosquito in an efficient manner. The use of plants by man with insecticide purposes dates back to early human history. Due to their environmental advantages, the use of insecticides of vegetable origin in pest management has been increasing . Among plants with potential activity against mosquitoes, Nim or Neem (
3.3. Biological agents
Among biological agents used for mosquito control can be mentioned derivatives of viruses, bacteria, and fungi. Entomopathogenic virus spreads from one insect generation to the next causing paralysis and eventually death on mosquito larvae being more effective in the first stage of development . Within bacteria, only reports of
The biological control of mosquito larvae with predators and other biological control agents could be a more effective and environmentally friendly strategy, thus avoiding the use of synthetic chemicals and the consequent environmental damage . Among them, some insects and vertebrates such as fish, amphibians, and some mammals have the potential to control mosquito disease–vector populations. Within vertebrates, amphibians, bats, and fish have been used to control populations of mosquito. For example, using larvivorous fish species, control of mosquito larvae in deposits used to store water has been achieved . Moreover, bats are responsible for capturing flying insects such as mosquitoes at night; similarly, toads and frogs consume large numbers of insects, slugs, worms, and other invertebrates . However, the use of frogs and tadpoles for disease vector control is still largely unexplored.
4. Development of resistance to chemical insecticides
Insecticide resistance is defined as the development of the ability of a insect population to tolerate doses of an insecticide, which would be lethal to the majority of individuals in a normal population of the same species and is also the result of pressure of positive selection exerted by the insecticide on the low frequency genes initially present in the vector insect . Therefore, the development of resistance by mosquito disease vectors is of international concern due to the increase worldwide exchange of plant matter that mosquitoes can spread to other parts of the world, spreading resistance genes of the plagues that they have.
Most mosquito vector control programs of diseases in humans are mainly based on the use of chemical insecticides by outdoor spraying, impregnated nets, or indoor residual spraying . Thereon, the use of insecticides has helped to eradicate insect-borne diseases. In this regard, since 1950, different classes of insecticides have been successively used. Organophosphates and pyrethroid insecticides have been used to control mosquito populations in their larval and adult stages. However, more recently, the disease vector control programs are based largely on the use of synthetic pyrethroid insecticides, which are recommended by the WHO only for impregnated nets . However, the massive use of pesticides has caused detrimental effects on the agroecosystem, such as the acquisition of resistance, pest resurgence, and environmental pollution. Resistance has developed in more than 84 species of mosquitoes for each of the groups of toxicological insecticides . Furthermore, it was found that insecticide residues accumulated in plants often end up in water bodies where mosquito larvae feeding on such plant debris or grow in water bodies enriched with plant compounds and interactions between these xenobiotics generate tolerance to insecticides or promote detoxification pathways of these insecticides against mosquitoes . In addition to abiotic factors, biotic interactions that occur among mosquitoes, the pathogens that they transmit and their microbiome (microbes living in the mosquito) may also occur . These vary from symbionts to entomopathogen opportunistic organisms that are able to affect various physiological host processes, such as detoxification systems  or the opposite effect leading to the appearance of insecticide resistance . Furthermore, allelochemicals inducing enzyme production in insects can increase their tolerance to pesticides . On the other hand, other studies have shown that the degree of development of a plant can affect insecticide resistance in insects .
There are two main mechanisms by which mosquito vectors can develop resistance to insecticides: alterations in the target site of action and metabolic resistance, also called increased rate of detoxification of insecticides . Other less common mechanisms that develop resistance in insects are the resistance per behavior and the resistance per decreased penetration through the cuticle or cross resistance .
4.1. Resistance mechanisms
Each insecticide triggers the selection of one or more mechanisms of resistance; in addition, an unknown number of behavioral changes in adults. For instance, changes in the target site of action are produced when no silent mutations occur in structural genes that produce an alteration of amino acids responsible for anchoring the insecticide at a specific site. For example, resistance have been reported by altering the voltage-dependent sodium channel that is the target site of action for pyrethroids and organochlorines, such as DDT, and in the insensitive acetylcholinesterase, which is the target site of action for organophosphate and carbamate . Furthermore, the metabolic detoxification is an acquired resistance mechanism, which is regulated by the activity of certain oxidized enzymes such as mixed function oxidase, esterases, glutathione S-transferases, and in specific cases DDT-dehidroclorinase. Mixed function oxidase represents an important detoxification mechanism in the degradation of carbamates; moreover, esterases have an important role in the degradation of phosphorus insecticides . Meanwhile, the metabolic resistance occurs through the increase in the detoxification of the insecticide. The most important form of metabolic resistance is given by detoxifying enzymes type glutathione S-transferase, mixed function oxidases, and esterases .
On the other hand, cross resistance can occur in two ways, positive and negative. The positive cross resistance refers to resistance to several insecticides due to expression in a single resistance mechanism . Therefore, cross resistance occurs when a single gene confers resistance to a number of chemicals in the same group, such as
Furthermore, multiple resistances occur when two or more resistance mechanisms independently selected are operating in the same insect . However, the term multiple resistances not necessarily involve the cross-resistance term because an insect may be resistant to two or more insecticides, and each resistance can be attributed to different mechanisms . Consequently, each additional mechanism of resistance leads to a wide cross resistance, which restricts the number of possible alternatives for the control and in extreme conditions, leading to highly resistant populations to virtually all available insecticides .
Mosquito-borne diseases are influenced by biological, ecological, social, and economic factors. Unfortunately, in most cases, deaths occur in rural areas where medical care is inadequate because resources are limited. Some of the mosquito-borne disease symptoms are mild and easy to treat; however, for other disease, antiviral drugs and antibiotics are not effective for controlling the virus, and there is still no vaccine available for prevention. One of the strategies used as a preventive measure to control the spread of diseases is the elimination of mosquitoes and their breeding sites. The main strategy for the elimination of mosquitoes is the use of chemical insecticides. However, their control is complicated because the frequent use of chemical insecticides generates resistance and the insecticides decrease their effectiveness. The use of plants, fungi, and bacteria with potential activity have some beneficial effects for the environment, but its duration is limited and some mosquitoes develop high resistance. A promising alternative is the use of chemicals and natural insecticides intended to modify the normal functioning of the mosquitoes that transmit diseases and which do not affect the environment.