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  • MK-8745 australia br Conclusions br Introduction Today just

    2020-01-14


    Conclusions
    Introduction Today – just as for the past 50 years – the most commonly used repellent in the world is DEET (Fradin, 1998; Pickett et al., 2008). The active ingredient, N,N-Diethyl-m-toluamide, is an oily synthetic substance applied topically to the skin in order to alter the host feeding behaviors of diverse blood sucking arthropods, including fleas, black flies, mosquitoes and ticks. Initially developed for use by United States military in 1946 and registered for commercial use about a decade later (Fradin, 1998; Katz et al., 2008), DEET’s formulation has undergone many changes over the years to improve its smell, texture, strength and duration of activity. Almost paradoxically, extensive research has been carried out to determine the effectiveness of the repellent and safe levels/duration of exposure, but its mode of action and molecular targets of the active ingredient remain poorly understood. Given DEET’s integral role in the prevention of vector-borne infectious diseases and concerns regarding the evolution of resistance (Stanczyk et al., 2010; Stanczyk et al., 2013), it is imperative that inroads are made towards elucidating the underlying basis of DEET repellence. Repellents do not kill arthropod pests; rather, they generally work by blocking/modulating the host-seeking (i.e., chemosensory) machinery of the arthropod, preventing it from coming into contact and feeding on humans. While many theories exist, the two predominant hypotheses for the mode of action of DEET are 1) it operates as a “confusant” by acting in conjunction with host odors to drive repellency; or 2) it is perceived as a harmful/adverse odor by the arthropod and is therefore avoided (reviewed in DeGennaro, 2015). Fundamentally based on these theories, some progress has been made towards deciphering the molecular targets (olfactory and gustatory) involved in DEET avoidance in flies, mosquitoes and nematodes (Ditzen et al., 2008; Lee et al., 2010; Pellegrino et al., 2011; Kain et al., 2013; DeGennaro et al., 2013; Dennis et al., 2017). Evidence is also accumulating for novel mechanisms of repellence involving the inhibition of detoxification (cytochrome P450) MK-8745 australia (Ramirez et al., 2012; Abd-Ella et al., 2015) or cholinesterases (Corbel et al., 2009). However, documentation of the specific genes and pathways associated with DEET avoidance in ticks is still in its infancy. Lacking conventional eyesight, antennae and a proboscis, ticks possess sensory innovations used to locate and attach to their vertebrate hosts. The main sensory organ, which is unique to ticks, is the Haller’s organ. Located on the first tarsus on their foremost pair of legs, the Haller’s organ specializes in behavior related to host seeking, infrared detection, body position and mating (Carr et al., 2017; Josek et al., 2018; Mitchell et al., 2017). Their other central sensory organ are the palps, which are found on the mouthparts (chelicerae) and mainly associated with anchoring and chemosensation (Renthal et al., 2017). While studies are slowly accruing, it is not currently understood how ticks detect repellents, or the relative importance of olfaction versus tactile chemoreception in repellency. There is evidence that olfaction is at least partially involved (Dautel et al., 1999; Mcmahon et al., 2003; Sonenshine and Roe, 2013), and the Haller’s organ has been implicated in spatial repellency of DEET (Carr et al., 2017). Moreover, the palps are also thought to be involved in repellency through direct contact with repellent via gustatory sensilla (Bissinger and Roe, 2014). The American dog tick, Dermacentor variabilis, is principally found in the United States, east of the Rocky Mountains. Since the 1940s, its range distribution has expanded into Canada, east of Saskatchewan (Matheson, 1950). In Manitoba, it is far and away the most abundant species of human-biting tick, ubiquitously found in the southern part of the province from April to June (Bishopp and Trembley, 1945; Dergousoff et al., 2013). D. variabilis feeds on the blood of a variety of mammalian hosts, including dogs, rabbits, raccoons, rats, mice, porcupines, squirrels, voles and humans (Carroll and Nichols, 1986; Koehler et al., 2018). In addition to its pest status, D. variabilis is of particular medical importance in North America since it is the primary vector of the pathogens causing Rocky Mountain spotted fever (RMSF) (Rickettsia rickettsii) (Burgdorfer, 1975) and tularemia (Francisella tularensis) (Reese et al., 2010). As there are no effective vaccines licensed and MK-8745 australia currently available against these infectious diseases, prevention is predominately achieved through the widespread use of repellents, such as DEET.