**1.2. Ecology of** *Aedes* **mosquitoes**

#### *1.2.1. Aedes aegypti*

tropical regions of the world and well beyond the Arctic Circle [1]. There are two subfamilies of Culicidae, that is, the Anophelinae (3 genera) and the Culicinae (110 genera). The subfamily Culicidae, *Aedes* is the largest tribe of mosquitoes with 1256 species classified into 10 genera: Aedes sensu (931), Armigeres (58), Eretmapodites (48), Haemagogus (28), Heizmannia (38),

The public health concern of *Aedes* mosquitoes particularly *Ae. aegypti* and *Ae. albopictus* in the transmission of arboviruses such as dengue virus, chikungunya virus, ZIKV virus, and yellow fever virus is kept on increasing globally. Over half of the world's population is at risk of dengue and chikungunya infections [3]. The Caribbean, South America, and Europe are no longer spared from chikungunya infection, a disease which was previously limited to Africa and Asia [3]. According to the World Health Organization, about 2.5 billion people globally live in dengue endemic regions [4]. Dengue is the most worldwide important mosquito-transmitted viral infection [4]. Over 100 countries in Africa, North and South America, Southeast Asia, Europe, and the Pacific are reported to have had severe dengue outbreaks [5]. The annual occurrence of dengue fever infections ranges from 50 to 100 million with which around 500,000 facing severe morbidity causing to over 20,000 mortalities, pediatrics beings the most cases [5]. The chikungunya virus infections (CHIKV) have been documented in over 60 countries in Asia, Africa, Europe, and the Americas [6]. The estimated number of chikungunya cases in Americas in 2016 was 693,000, and Zika virus (ZIKV) disease was 500,000 [6, 7]. Yellow fever cases in Africa were 130,000 with an estimated 31,000 annual disability adjusted

About 80% of the world's population is at risk for at least of exposure to one vector-borne disease; these diseases account for about 17% of the estimated global burden of communicable diseases and cause over 700,000 deaths annually, affecting disproportionately poorer populations [6, 9]. They hamper economic development through direct medical costs and indirect costs such as the loss of productivity and tourism. The social, demographic, and environmental factors strongly influence transmission patterns of vector-borne pathogens. Vector control is an important component for decision science in the prevention and control of vector-borne disease approaches. Consequently, the global distribution and ecology of these vectors and the geographical determinants of their ranges are essential in order to be effective. Therefore, it is important to work out where these mosquito species are found around the globe to identify the areas at risk. It is also important to predict where these species could become established if they were introduced, in order to identify areas that could become at risk in the future.

*Ae. aegypti* and *Ae. albopictus* are worldwide distributed between 35° N and 35° S, latitudes that roughly correspond to a 10°C winter isotherm which appears to be the limiting temperatures that the species can tolerate while overwintering [5]. The species are highly adapted to urban environments, breeding in stagnant water found in manufactured containers, garbage heaps, and tyres. However, the distribution of *Ae. albopictus* has been highly biased to temperate climates [10] though the vector is now widely distributed throughout the Americas

(excluding Canada), Europe, Asia, Africa, Australia, and the Pacific [11].

Opifex (2), Psorophora (49), Udaya (3), Verrallina (95), and Zeugnomyia (4) [2].

life years and 500 deaths [8, 9].

40 Dengue Fever - a Resilient Threat in the Face of Innovation

**1.1.** *Aedes* **distribution**

*Ae. aegypti* is an arthropod closely associated with humans and their habitats. They are mostly anthropophilic [13] with high preference to the urban environment [14]. They get blood meals from human, and human creates conducive environment for their population growth through up haphazardly disposal of water-holding containers/obsoletes around our homes. The mosquito lays her eggs on the sides of containers with water, and eggs hatch into larvae after a rain or flooding. A larva changes into a pupa in about a week and into a mosquito in 2 days. The *Aedes* main habitat is aquatic, and they can thrive better from tree cavities to toilets. People also furnish shelter as *Ae. aegypti* preferentially rests in darker cool areas, such as closets leading to their ability to bite indoors.

*Ae. aegypti* has adaptations to the environment that makes them highly resilient, or with the ability to rapidly bounce back to initial numbers after disturbances resulting from natural phenomena (e.g., droughts) or human interventions (e.g., control measures). One such adaptation is the ability of the eggs to withstand desiccation (drying) and to survive without water for several months on the inner walls of containers. For example, if we were to eliminate all larvae, pupae, and adult *Ae. aegypti* at once from a site, its population could recover 2 weeks later as a result of egg hatching following rainfall or the addition of water to containers harboring eggs.

It is likely that *Ae. aegypti* is continually responding or adapting to environmental change. For example, it was recently found that *Ae. aegypti* is able to undergo immature development in broken or open septic tanks resulting in the production of hundreds or thousands of *Ae. aegypti* adults per day. In general, it is expected that control interventions will change the spatial and temporal dispersal of *Ae. aegypti* and perhaps the pattern of habitat utilization.

#### *1.2.2. Aedes albopictus*

*Aedes albopictus* (*Stegomyia albopicta*), from the mosquito (Culicidae) family, also known as (Asian) tiger mosquito or forest mosquito, is a mosquito native to the tropical and subtropical areas of Southeast Asia; however, in the past few decades, this species has spread to many countries through the transport of goods and international travel [15]. The eggs of *Ae. albopictus* are desiccation resistant, which enhance survival in inhospitable environments [16]. *Ae. albopictus* is among the aggressive outdoor species of mosquito, and they are day biter that has a very broad host range and attacks humans, livestock, amphibians, reptiles, and birds [17]. Their biting rate level can be as high as 30 to 48 bites per hour [18]. *Ae. albopictus* survives at a large range of temperatures [19].


**Table 1.** The *Aedes aegypti* and *Ae. albopictus* distribution globally. *Ae. albopictus* is a treehole mosquito, and so its breeding places in nature are small, restricted, shaded bodies of water surrounded by vegetation. It inhabits densely vegetated rural areas. However, its ecological flexibility allows it to colonize many types of man-made sites and urban regions. It may reproduce in cemetery flowerpots, birdbaths, soda cans and abandoned containers, and water recipients. Tyres are particularly useful for mosquito reproduction as they are often stored outdoors and effectively collect and retain rainwater for a long time. The addition of decaying leaves from the neighboring trees produces chemical conditions similar to tree holes, which provides an excellent substrate for breeding. *Ae. albopictus* can also establish and survive throughout nonurbanized areas lacking any artificial containers, raising

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43

*Aedes* mosquito species, *Ae. aegypti*, and *Ae. albopictus* are major public health concern due to

regions and is largely responsible for vector-borne arboviral infections, yellow fever virus (YFV), ZIKV, dengue virus (DENV), West Nile virus (WNV), CHIKV and transmission, and

due to its anthropophilic behavior, well domesticated, and adapted to survive in different

The *Aedes* spp. mosquitoes are known to have a complex life cycle involving aquatic and

order for the eggs to develop. The vector needs water to lay their eggs in the preferred breeding container, including tyres, water storage containers, disposed tyres, coconut shells, and flowerpots [20]. *Aedes* spp. prefers to lay their eggs on the inner wet walls of containers with water, hence the name "container breeder". The development of the

from the eggs. The larva survival depends on the microorganisms found in the aquatic environment. Larvae go through developmental stages (stage 1–4) in which they molt or shed their skin; these larval stages are called the first to fourth instars [20]. When a larva is a fully grown fourth instar, it undergoes metamorphosis into a new form called a pupa in approximately 4 days, the "cocoon" stage for the mosquito. This developmental stage of the mosquitoes also occurs in the aquatic environment. After 1–2 days, the fully developed adult mosquito forms and breaks through the skin of the pupa and a fully grown adult emerges. The adult mosquito is able to fly and has a terrestrial habitat inhabiting inside

Interestingly, *Aedes* has developed a survival mechanism during the dry seasons; the eggs can enter a dormancy (quiescence) for up to 8 months at the end of embryogenesis [21]. If the habitat is dry, the eggs remain dormant but after rainfall, the eggs hatch and develop

ment continues [20]. In addition to being desiccation resistant, *Aedes* spp. is well adapted to produce, eggs can withstand months of dormancy, so-called "extended quiescence" in the unfavorable abiotic environment [21]. The male *Aedes* spp. mosquitoes feed on flowers' nectar or plant juices, unlike the female that needs a blood meal [22]. The vector becomes infected

2]. Mosquitoes acquire the infection after a blood-meal form the host in

3]. *Ae. aegypti* mosquito is widespread in (sub-)tropical

1, 3].

**1**) where the larvae hatch


7]. The *Ae. aegypti* is known to have high vectorial capacity

additional public health concerns for rural areas [17].

3,

geographical regions including Africa, Americas, Asia, and Europe [

eggs occurs between 2 and 7 days in the aquatic phase (**Figure**

*1.2.3. Aedes mosquitoes life cycle*

outbreaks in various regions [

and outside households [20].

terrestrial life [

their role in transmission of diseases [

*Ae. albopictus* is a treehole mosquito, and so its breeding places in nature are small, restricted, shaded bodies of water surrounded by vegetation. It inhabits densely vegetated rural areas. However, its ecological flexibility allows it to colonize many types of man-made sites and urban regions. It may reproduce in cemetery flowerpots, birdbaths, soda cans and abandoned containers, and water recipients. Tyres are particularly useful for mosquito reproduction as they are often stored outdoors and effectively collect and retain rainwater for a long time. The addition of decaying leaves from the neighboring trees produces chemical conditions similar to tree holes, which provides an excellent substrate for breeding. *Ae. albopictus* can also establish and survive throughout nonurbanized areas lacking any artificial containers, raising additional public health concerns for rural areas [17].

#### *1.2.3. Aedes mosquitoes life cycle*

**Country**

*Ae. aegypti*

Americas

Brazil

USA Mexico

Cuba Argentina Trinidad and

152

Tobago

Venezuela Colombia Puerto Rico

Peru

*Ae. albopictus*

Americas

Brazil

USA Mexico Cayman Islands

Haiti Guatemala

Venezuela

Colombia

Cuba Puerto Rico

> **Table 1.**

The *Aedes aegypti* and *Ae. albopictus* distribution globally.

3

3

Israel Lebanon Note: This table was contributed by Kramer a leading author of the paper published in E-life journal (https://doi.org/10.7554/eLife.08347.003).

17 15

3

7

12

13

15

50

1594

3441

Europe/

Italy Madagascar

Cameroon

France Gabon Albania Mayotte

Greece

203

58 42 37 27 22 21 18

Asia/

Taiwan Malaysia Indonesia

India Japan Thailand Singapore Lao People's Democratic

Republic

Philippines

Viet Nam

22

18

15,339

186

161

150

97

82

44

26

Oceania

Africa

89

120

128

130

Madagascar

Gabon Mayotte Sierra Leone

28 27 20 20

Malaysia Singapore Philippines

Cambodia

112

44

36

29

170

177

411

436

5044

Europe/

Senegal Cameroon

Kenya United Republic of

44

Tanzania

Côte d'Ivoire

Nigeria

40 35

Australia Viet Nam

282

223

112

55 52

Asia/

Taiwan Indonesia

Thailand

India

9490

603

495

423

42 Dengue Fever - a Resilient Threat in the Face of Innovation

Oceania

Africa

**Occurrences**

**Country**

**Occurrences**

**Country**

**Occurrences**

*Aedes* mosquito species, *Ae. aegypti*, and *Ae. albopictus* are major public health concern due to their role in transmission of diseases [3]. *Ae. aegypti* mosquito is widespread in (sub-)tropical regions and is largely responsible for vector-borne arboviral infections, yellow fever virus (YFV), ZIKV, dengue virus (DENV), West Nile virus (WNV), CHIKV and transmission, and outbreaks in various regions [3, 7]. The *Ae. aegypti* is known to have high vectorial capacity due to its anthropophilic behavior, well domesticated, and adapted to survive in different geographical regions including Africa, Americas, Asia, and Europe [1, 3].

The *Aedes* spp. mosquitoes are known to have a complex life cycle involving aquatic and terrestrial life [2]. Mosquitoes acquire the infection after a blood-meal form the host in order for the eggs to develop. The vector needs water to lay their eggs in the preferred breeding container, including tyres, water storage containers, disposed tyres, coconut shells, and flowerpots [20]. *Aedes* spp. prefers to lay their eggs on the inner wet walls of containers with water, hence the name "container breeder". The development of the eggs occurs between 2 and 7 days in the aquatic phase (**Figure 1**) where the larvae hatch from the eggs. The larva survival depends on the microorganisms found in the aquatic environment. Larvae go through developmental stages (stage 1–4) in which they molt or shed their skin; these larval stages are called the first to fourth instars [20]. When a larva is a fully grown fourth instar, it undergoes metamorphosis into a new form called a pupa in approximately 4 days, the "cocoon" stage for the mosquito. This developmental stage of the mosquitoes also occurs in the aquatic environment. After 1–2 days, the fully developed adult mosquito forms and breaks through the skin of the pupa and a fully grown adult emerges. The adult mosquito is able to fly and has a terrestrial habitat inhabiting inside and outside households [20].

Interestingly, *Aedes* has developed a survival mechanism during the dry seasons; the eggs can enter a dormancy (quiescence) for up to 8 months at the end of embryogenesis [21]. If the habitat is dry, the eggs remain dormant but after rainfall, the eggs hatch and development continues [20]. In addition to being desiccation resistant, *Aedes* spp. is well adapted to produce, eggs can withstand months of dormancy, so-called "extended quiescence" in the unfavorable abiotic environment [21]. The male *Aedes* spp. mosquitoes feed on flowers' nectar or plant juices, unlike the female that needs a blood meal [22]. The vector becomes infected

cycle of the adult vector including the longevity, fecundity body mass, and vectorial competence [26]. For instance, some algae species, *Cladophora sp.*, *Chlorella ellipsoidea*, and *Rhizoclonium hieroglyphicum*, were shown to exhibit larvicidal properties that affect the development of the immature stages [25]. Evidence suggests that the developmental stage from first instar larval stage to adult mosquito is faster when the organic matters are abundant in the breeding container, in addition, the survival rate of the immature stage is enhanced [27]. In contrast, low concentration or exhaustion of the nutrients is required to trigger pupation presumably in response to the increasing level of ecdysteroid hormone [3, 28, 29]. Temperature is important for the survival larva density and competence of the *Ae. aegypti*. In areas where the temperature is warmer, the development of the aquatic stage temperature was associated with shorter development time from hatch to the emergence of the adult mosquito [4]. Similarly, longer light exposure was also shown to shorten the development time [30]. The evidence explains the widespread distribution and pattern of *Ae. aegypti* in (sub-)tropical regions. Furthermore, evidence suggests increasing *Ae. aegypti* abundance in urban areas leading to outbreaks [31]. It is evident that developing countries are becoming more urbanized; however, poor city planning and sanitation have increased mosquito breeding sites [7]. The "ecological plasticity" exhibited by the vector is arguably among the reasons for reason that explain it its worldwide

Ecology of *Aedes* Mosquitoes, the Major Vectors of Arboviruses in Human Population

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The emergence of insecticide resistance to multiple classes of insecticides has been widely reported in *Ae. aegypti* in different regions [24, 32–34]*.* WHO defines resistance as the ability of mosquitoes to survive exposure to a standard dose of insecticide; this ability may be the result of physiological or behavioral adaptation [35]. The emergence and spread of resistance to the main insecticides could compromise the effectiveness of the preventive measures, operational

There are three major categories of insecticide resistance that have been described, namely, physiological resistance (target-site resistance and metabolic resistance) and behavioral avoidance. First, physiological resistance may develop due to the target-site resistance. Target site mutations are known to cause amino acid substitutions, which could affect the influx of insecticides into the target site. This may compromise the action of the insecticide rendering the vector tolerant or fully resistant to the insecticide. Another form of physiological resistance is due to metabolic resistance due to detoxification of insecticides by cytochrome P450 monooxygenases which allow the resistant vector to metabolize insecticides [36]. Glutathione S-transferases (GSTs) and carboxylesterases (ESTs) are also described in this process. Over expression of P450s was associated with insecticide resistance in diverse vector species including *Ae. aegypti* [37]. The resistant vectors accumulate high levels of efficient enzymes that detoxify the toxins. The second mechanism of resistance is known as behavioral adaptation or avoidance of the vector, this is well characterized in *Anopheles* mosquitoes. Therefore, monitoring insecticide resistance is crucial in the implementation of

widespread and success as a human vector.

implementation of control programs, and outbreak management.

**1.3. Insecticide resistance in** *Aedes* **spp.**

**1.4. Mechanisms of insecticide resistance**

vector control strategies.

**Figure 1.** *Aedes* mosquito life cycle in aquatic and terrestrial phases.

when they feed on infected humans, and transmission may occur when the vector bites the host, which is believed to be promoted by mosquito salivary protein.

Historically, *Ae. aegypti* is believed to have originated from zoophilic subspecies *Ae. Aegypti formosus* inhabiting forests in sub-Saharan Africa [12]. This subspecies is found in the forests, breed in the tree holes and feeding on other mammals. The evolution of the ancestral *Ae. aegypti* resulted in the domesticated *Ae. aegypti* subspecies with a strong preference for biting humans and breed in man-made containers [20]. This evolved as the dominant vector of several diseases including yellow fever and DENV, ZIKV infections worldwide. The domestication of the vector was associated with the human migrations, trade, transportation, and urbanization [20, 23]. The domestic *Ae. aegypti* thrive in (sub-)tropical and temperate regions and can inhabit either terrestrial or aquatic depending on the stages of the growth. *Ae. aegypti* is primarily a container breeding vector and is known to predominate in urban areas where there is the vast composition of favorable man-made breeding container environment [20]. The breeding sites range from natural to artificial including vegetation, discarded tyres, discarded containers, bottle tops, water storage containers (especially in places with erratic tap water supply), flowerpots and vases, metal drums, and coconut shells [9, 24]. Other breeding sites include the open or unsealed septic tanks, water wells, and water meters. The ecological factors determine the crucial characteristics of different stages of the life and eventually its success. The *Ae. aegypti* larvae feed on nutritious materials available in the aqueous phase in the breeding containers including the plant particles, animal debris, and phytoplankton such as microalgae found in the water-filled containers [25]. The ecological characteristics are important in the life cycle of the adult vector including the longevity, fecundity body mass, and vectorial competence [26]. For instance, some algae species, *Cladophora sp.*, *Chlorella ellipsoidea*, and *Rhizoclonium hieroglyphicum*, were shown to exhibit larvicidal properties that affect the development of the immature stages [25]. Evidence suggests that the developmental stage from first instar larval stage to adult mosquito is faster when the organic matters are abundant in the breeding container, in addition, the survival rate of the immature stage is enhanced [27]. In contrast, low concentration or exhaustion of the nutrients is required to trigger pupation presumably in response to the increasing level of ecdysteroid hormone [3, 28, 29]. Temperature is important for the survival larva density and competence of the *Ae. aegypti*. In areas where the temperature is warmer, the development of the aquatic stage temperature was associated with shorter development time from hatch to the emergence of the adult mosquito [4]. Similarly, longer light exposure was also shown to shorten the development time [30]. The evidence explains the widespread distribution and pattern of *Ae. aegypti* in (sub-)tropical regions. Furthermore, evidence suggests increasing *Ae. aegypti* abundance in urban areas leading to outbreaks [31]. It is evident that developing countries are becoming more urbanized; however, poor city planning and sanitation have increased mosquito breeding sites [7]. The "ecological plasticity" exhibited by the vector is arguably among the reasons for reason that explain it its worldwide widespread and success as a human vector.

#### **1.3. Insecticide resistance in** *Aedes* **spp.**

**Figure 1.** *Aedes* mosquito life cycle in aquatic and terrestrial phases.

44 Dengue Fever - a Resilient Threat in the Face of Innovation

host, which is believed to be promoted by mosquito salivary protein.

when they feed on infected humans, and transmission may occur when the vector bites the

Historically, *Ae. aegypti* is believed to have originated from zoophilic subspecies *Ae. Aegypti formosus* inhabiting forests in sub-Saharan Africa [12]. This subspecies is found in the forests, breed in the tree holes and feeding on other mammals. The evolution of the ancestral *Ae. aegypti* resulted in the domesticated *Ae. aegypti* subspecies with a strong preference for biting humans and breed in man-made containers [20]. This evolved as the dominant vector of several diseases including yellow fever and DENV, ZIKV infections worldwide. The domestication of the vector was associated with the human migrations, trade, transportation, and urbanization [20, 23]. The domestic *Ae. aegypti* thrive in (sub-)tropical and temperate regions and can inhabit either terrestrial or aquatic depending on the stages of the growth. *Ae. aegypti* is primarily a container breeding vector and is known to predominate in urban areas where there is the vast composition of favorable man-made breeding container environment [20]. The breeding sites range from natural to artificial including vegetation, discarded tyres, discarded containers, bottle tops, water storage containers (especially in places with erratic tap water supply), flowerpots and vases, metal drums, and coconut shells [9, 24]. Other breeding sites include the open or unsealed septic tanks, water wells, and water meters. The ecological factors determine the crucial characteristics of different stages of the life and eventually its success. The *Ae. aegypti* larvae feed on nutritious materials available in the aqueous phase in the breeding containers including the plant particles, animal debris, and phytoplankton such as microalgae found in the water-filled containers [25]. The ecological characteristics are important in the life The emergence of insecticide resistance to multiple classes of insecticides has been widely reported in *Ae. aegypti* in different regions [24, 32–34]*.* WHO defines resistance as the ability of mosquitoes to survive exposure to a standard dose of insecticide; this ability may be the result of physiological or behavioral adaptation [35]. The emergence and spread of resistance to the main insecticides could compromise the effectiveness of the preventive measures, operational implementation of control programs, and outbreak management.

#### **1.4. Mechanisms of insecticide resistance**

There are three major categories of insecticide resistance that have been described, namely, physiological resistance (target-site resistance and metabolic resistance) and behavioral avoidance. First, physiological resistance may develop due to the target-site resistance. Target site mutations are known to cause amino acid substitutions, which could affect the influx of insecticides into the target site. This may compromise the action of the insecticide rendering the vector tolerant or fully resistant to the insecticide. Another form of physiological resistance is due to metabolic resistance due to detoxification of insecticides by cytochrome P450 monooxygenases which allow the resistant vector to metabolize insecticides [36]. Glutathione S-transferases (GSTs) and carboxylesterases (ESTs) are also described in this process. Over expression of P450s was associated with insecticide resistance in diverse vector species including *Ae. aegypti* [37]. The resistant vectors accumulate high levels of efficient enzymes that detoxify the toxins. The second mechanism of resistance is known as behavioral adaptation or avoidance of the vector, this is well characterized in *Anopheles* mosquitoes. Therefore, monitoring insecticide resistance is crucial in the implementation of vector control strategies.

#### *1.4.1. Physiological resistance in Aedes spp.*

In Tanzania, like many other African settings, there is limited information on the *Ae. aegypti* resistance, most of the resistance data were collected mainly in the Americas and Asia. Our recent study in Dar es Salaam [24] demonstrated that the majority of *Ae. aegypti* strains were resistant to pyrethroid class of insecticide; mortality ranging from 83 to 92% in Dar es Salaam City. Data on molecular markers of resistance are scarce; however, studies elsewhere have correlated the occurrence of the knockdown resistance (kdr) mutations and resistance to pyrethroid and DDT [29, 34, 37, 38].

programs since insecticide resistance could spread and render the insecticides ineffective. Therefore, more studies to assess the current susceptibility status of insecticides used for vec-

Ecology of *Aedes* Mosquitoes, the Major Vectors of Arboviruses in Human Population

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*Ae. aegypti* mosquito is a major vector of dengue virus represented by four closely related serotypes called dengue 1, 2, 3, and 4 cause different illness including dengue fever, dengue shock syndrome, and dengue haemorrhagic fever. Dengue virus (DENV) belonging to the family

Transmission of dengue fever (DF) occurs when a female *Aedes* spp. mosquito obtains its blood meal from an infected person during the period of viraemia. Mosquito-borne viruses multiply in both invertebrate and vertebrate cells where they cause cytopathic effects and cell destruction. Vector mosquitoes become infected when they feed on blood of a viremic vertebrate host in which there are sufficient circulating viral particles to provide an infectious

A mosquito with salivary gland infection may transmit infectious virions during salivation as it probes the tissues of another vertebrate host. Transovarial transmission of virions occurs from the female mosquito to her progeny, and females of the next generation can transmit the virus orally without having been infected through blood feeding. There is also a venereal transmission of some arboviruses from male to female mosquito as observed and reported by

tor control are needed to describe the status to support control strategies.

**2. Disease transmission by** *Aedes aegypti*

Flaviviridae and genus *Flavivirus* [48].

Amarasinghe and others [49] (**Figure 2**).

**Figure 2.** Arboviral transmission cycle vectored by *Aedes* mosquitoes.

dose to the mosquito.

The mechanism of action of the pyrethroid compounds is through their toxic effect and subsequent disruption of the VGS channels in the insect nervous system [32]. The evidence suggests that *Ae. aegypti* resistance to pyrethroids is conferred by the *kdr* mutations in the VGS channel [29, 39]. Nonsynonymous mutations in *kdr* gene are associated with insecticide resistance to DDT and pyrethroids on codon V1016I and F1534C in domains II and III of the VSG channel in *Aedes* spp. [40]. Other studies demonstrated the role of *kdr* gene mutation I1011M/V and F1269C in association with *Ae. aegypti* resistance [33, 34, 41]. In African settings, the occurrence of F1534C in concurrence with the V1016I mutation was also observed in Ghanaian *Ae. aegypti* population [42]. The more recent study demonstrated the significant role of *kdr* mutation V410L alone or in combination with the F1534C in reducing the sensitivity of *Ae. aegypti* to both type I (e.g., permethrin) and type II (e.g., deltamethrin) pyrethroids [32].

In addition to the *kdr* mutations, metabolic resistance is also know to lead to a physiological resistance due to the increase in the synthesis of detoxifying enzymes or in their specificity to metabolize the insecticide, both resulting in an enhancement of the insect detoxifying capacity of the vector [43, 44]. The P450 monooxygenases were shown to play a significant role in modulating resistance as revealed by high-throughput assays, by comparing the overall profile at genomic and transcriptome levels between resistant and susceptible populations [37]. A study that characterized several P450s, four CYP's, 9 J32, 9 J24, 9 J26, and 9 J28, conferring insecticide resistance in *Ae. aegypti* [37]. The CYPs were shown to be capable of metabolizing deltamethrin and permethrin; two common pyrethroid-based insecticides are widely used in vector interventions. Furthermore, there is evidence on the role of glutathione transferase (GST) enzymes in conferring resistance to several classes of insecticides [45]. In *Ae. aegypti*, the GST occurs as a cluster of genes in chromosome 2 and is shown to play a significant role in the metabolism of DDT [46]. Over expression of the GST enzyme is associated with DDT and pyrethroid resistant in *Ae. aegypti* populations. We, therefore, characterized additional members of this class in *Ae. aegypti* and provide evidence for a role of two additional GSTs in conferring resistance to insecticides.

#### *1.4.2. Behavioral resistance in Aedes spp.*

Thus is defined as the ability of a vector to detect and escape from an insecticide-treated area and avoid the toxin. This type of resistance has been shown in different classes of insecticides, including organochlorines, organophosphates, carbamates, and pyrethroids [47]. It has been shown that vectors are capable of avoiding feeding if they come across certain insecticides or escape the area sprayed with the insecticides. There are currently limited studies exploring this mechanism of resistance in *Ae. aegypti.* This paucity of information could hamper control programs since insecticide resistance could spread and render the insecticides ineffective. Therefore, more studies to assess the current susceptibility status of insecticides used for vector control are needed to describe the status to support control strategies.
