Identification and validation of Zika virus receptor(s) in the midgut lumen of Aedes aegypti

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SUMMARY The central goal of this project is to identify Zika virus (ZIKV) receptor(s), generation ZIKV transmission incompetent transgenic mosquitoes that lack the receptor-encoding gene and identification of novel transmission blocking vaccine candidate(s). Transmission of arthropod-borne viruses (arboviruses) causes widespread and debilitating diseases across the globe. In the absence of effective licensed vaccines or therapeutic treatments of arboviruses, including ZIKV, control at the vector level is the most effective method to ameliorate the burden of these viruses. Before these viruses can be transmitted to humans, they must first infect the mosquito following a blood meal. Thus, investigations to understand ZIKV-mosquito interactions are of critical importance. In this proposal, we will identify specific molecules in the Aedes aegypti mosquito midgut that act as receptors and facilitators for ZIKV binding and establishment of infection. Identified candidate receptors will be validated in vivo by genetic ablation using CRISPR/Cas9 gene editing and subsequent oral challenge with an infectious ZIKV blood meal. Data generated in this study will assist in 1) the development of effective disease control measures, e.g. via the generation of transgenic mosquitoes that lack the receptor-encoding gene and would be incompetent for ZIKV transmission; and 2) identification of ZIKV receptor molecules in the mosquito midgut will provide new insights into the basic biology and molecular mechanisms underpinning the vector competency and mosquito- arboviral pathogen interactions. The proposed experiments are also significant because they provide the groundwork for future experiments that will determine whether the same receptor(s) is used by other arboviruses and other mosquito species.