A Biotechnology Platform for Fighting Mosquito-Borne Disease Transmission




Dalwadi, Dhwanil
Wang, Huanyu
Schetz, John


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Background: Zika, West Nile virus, dengue and malaria are infectious diseases transmitted by the bite of a mosquito. Thus, technologies that prevent biting will prevent infectious disease transmission. Octopamine is a biogenic amine that controls key physiological responses including those related to fine motor control. Since biting requires fine motor control, disruption of octopaminergic systems appears to be an attractive approach to prevent mosquito biting. Every year, over a billion mosquito-borne disease cases were reported and increasing resistance of mosquitoes to first-line control measures is a cause for growing concern. To address this concern we seek to discover and develop new chemical classes of arthropod octopamine receptor deterrents to prevent biting. Our hypothesis is that at mosquito octopamine receptor activators will prevent mosquito biting. Methodology: Cloned octopamine receptors from two species of mosquitoes Anopheles gambiae (AgOctR) and Aedes egypti (AeOctR) were functionally expressed in mammalian cells. The expression levels of these receptors were quantified using radioligand binding. The ability of octopamine and experimental compounds to active the Gq-PLC-IP3-Ca2+ signaling pathway was assessed by measuring changes in intracellular calcium. Results: Specific binding of a radioligand to cells transfected with mosquito OctR DNA confirmed the successful high expression of OctR protein from both genera of mosquitoes. Functional assays with the endogenous ligand octopamine showed the expressed receptors are truly octopamine receptors given the dose-response nature of the response and the ability of an OctR antagonist to block the response. High potency of octopamine at the receptors over tyramine confirmed these receptors as OctRs instead of closely related tyramine receptor. Robust Gq-PLC-IP3-Ca2+ signaling responses indicate these receptors are Gq-coupled consistent with their identity specifically as α-like OctRs. These systems were used to begin to characterize novel experimental compounds, some of which act as potent OctR agonists. Conclusions: In this study, we created cell lines stably expressing cloned mosquito OctRs and validated that the sequences code for bona fide α-like OctRs. Correlation of the agonistic effect of experimental compounds at these cloned mosquito OctR with protection against biting suggest that this molecular platform could serve as a useful biotechnology of discovering novel mosquito deterrents.