**4. Mosquito sensory system and olfactory signal transduction**

It is not difficult to admire that the multimodal sensory system of mosquitoes is the critical regulator of different behavioral processes and thus has a potential impact on disease transmission. In addition, the wide diversity of host preference in mosquitoes is governed by the different genetic makeup of individual species which has strong epidemiological consequences. Therefore, decoding species-specific molecular factors of the mosquitoes' olfactory system may unravel the mechanism of their behavioral plasticity. Two primary components of the chemosensory system are the peripheral system where the chemical information is detected and the central processing unit where the initial signal of odor is processed. The appendages present on the head of the mosquitoes act as the principal detection system, which includes paired antennae, paired maxillary palp, and a labium [8, 17]. These peripheral appendages are equipped with fine hair-like structures called the sensilla, which are distributed nonrandomly across these antennae, maxillary palp, and labium. The type and number of sensilla present on the olfactory organ are highly speciesspecific [8, 17]. Odorants are thought to penetrate through the numerous pores present on the wall of the sensilla and then traverse through the aqueous sensillar lymph towards the array of molecular receptors present on the dendrites of olfactory receptor neurons (ORNs) [18]. Binding of the diverse odorants with their cognate receptors either activates or inhibits the receptors by changing the ORN action potential. More than two decades of research on insect olfaction uncover several molecular factors that are responsible for odor detection and downstream signal transduction processes. These include odorant-binding proteins (OBPs), odorantdegrading enzymes (ODEs), odorant receptors (ORs), sensory neuron membrane proteins (SNMPs), G proteins, arrestins, and other signaling molecules [8].

### **4.1 Odorant-binding proteins and odorant-degrading enzymes**

Odorant molecules are hydrophobic in nature which require cargo to traverse through the sensillar lymph to reach the receptor molecules, which are present on the dendritic membrane [19–21]. This role is carried out by the odorant-binding proteins (OBPs), which act as a passive carrier of the chemical odorant molecules. OBPs are water-soluble globular proteins containing six α-helical domains with conserved cysteine residues [22]. The number of genes encoding different OBPs varied across different mosquito species and is also dependent on the number of odorant receptors [22]. The availability of this wide and diverse spectrum of OBPs in the insect's tissues facilitates their rapid adaptation in distinct environment. The OBP family broadly includes the pheromone-binding proteins (PBPs) which

*Sino-Nasal and Olfactory System Disorders*

**3. Mosquito navigation**

hundreds of chemicals.

consequently helps in food acquisition (**Figure 2**).

and discriminate among odorant molecules through olfactory system, (2) how the initial signal of odor is processed in the central nervous system/brain and the molecular factors responsible for feeding decision-making process, and (3) how the brain influences and regulates distant tissue such as salivary gland for salivation and

A sophisticated olfactory system of mosquitoes enables them to communicate and responds to the diverse array of biological and environmental chemical stimuli throughout their life cycle. They use olfactory cues for locating a food source (nectar sugar), finding a mate partner, locating oviposition site, and most importantly selecting a vertebrate host for blood-feeding. Among these olfactory-guided behaviors, searching and locating the desired plant for nectar-feeding involves both visual and chemical cues emanating from different plant species [13]. Volatiles such as monoand bicyclic monoterpenes are major floral odors for mosquito attraction, and lightercolored plant flowers have an additional benefit for successful sugar feeding [14]. But, detection of blood-feeding host requires the integration of olfactory, visual, thermal, and humidity cues [15, 16]. The pattern of host-seeking behavior and selection of a certain host are strictly species-specific. However, the navigation trajectory of all the

a.Female mosquitoes are engaged in random, non-oriented navigation until they encounter a plume of host odorants including skin emanates consisting of

b.Random navigation became oriented when a female mosquito detects fluctuation in the carbon dioxide concentration above the atmospheric measurement, caused by the addition of ~4% CO2 from human breath. The mosquito then follows the trail of odor plume and initiates to fly upwind in a zigzag pattern which drives mosquitoes to reach the odor source. The concentration gradient of different odorants, initiating from CO2 from long distance (> 10 m), overlaps with other host odors such as lactic acid and 1-octen-3-ol available at closer vicinity, which acts in a synergistic way to make the navigation successful.

*Mosquito navigation trajectory according to odor plume. The random, non-oriented navigation becomes oriented when mosquitoes sense a gradient of different host odors such as CO2, lactic acid, 1-octen-3-ol, etc. olfaction along with vision, thermosensation, and hygrosensation facilitates the navigation process and blood* 

blood-feeding mosquitoes may have some common events (**Figure 3**).

**76**

**Figure 3.**

*meal uptake.*

transport pheromones and different chemosensory proteins (CSPs) which are smaller in size but can bind with a broad spectrum of semiochemicals. In mosquitoes, the OBP genes are classified in three subfamilies: (i) classic OBPs that carry a conserved motif consisting of six cysteine residues; (ii) Plus-C OBPs which contain six additional cysteine residues with novel disulfide connectivity along with three classic OBP motifs; and (iii) atypical OBPs, the longest OBPs that contain a single classic OBP domain in its N-terminal which is extended by a C-terminal extension. Among these three subfamilies, Plus-C OBP class is more divergent in nature and has only been identified from Diptera *Anopheles*, *Culex*, and *Drosophila*; however, Hymenoptera and Lepidoptera did not possess these OBPs. The first OBP of mosquito origin was isolated from the antennae of female *Culex quinquefasciatus* (CquiOBP1) in the early twenty-first century [20, 23]. The availability of genome sequence of several mosquito species in the public domain facilitates the identification and characterization of this large family of OBP genes from different mosquito species, for example, the total number of 69 OBPs from *A. gambiae*, 111 OBPs from *A. aegypti*, 109 OBPs from *C. quinquefasciatus*, *and* 63 OBPs in *A. culicifacies* [20, 24, 25]. Activation of the chemosensory receptors by odorants also requires timely termination and desensitization of peripheral signaling to maintain sensitivity of ORN-based signaling [26, 27]. In this process, odorant-degrading enzymes (ODEs), particularly several esterases and cytochrome p450s, play a crucial role by terminating the odor-induced signal transduction processes [28–30].
