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Transmission of flaviviruses by hematophagous insects such as mosquitoes requires acquisition of the virus during blood feeding on the host, with midgut as the primary infection site. Here, we report that N-glycosylation of the E protein, which is conserved among most flaviviruses, is critical for the Zika virus (ZIKV) to invade the vector midgut by inhibiting the reactive oxygen species (ROS) pathway of the mosquito immune system. Our data further show that removal of the ZIKV E glycosylation site prevents mosquito infection by flaviviruses via the oral route, whereas there is no effect on infection by intrathoracic microinjection, which bypasses the midgut. Interestingly, the defect in infection of the mosquito midgut by the mutant virus through blood feeding is rescued by reduction of the ROS level by application of vitamin C, a well-known antioxidant. Therefore, our data demonstrate that ZIKV utilizes the glycosylation on the envelope to antagonize the vector immune defense during infection. IMPORTANCE Most flaviviruses, including Zika virus (ZIKV), are transmitted between hosts by arthropod vectors, such as mosquitoes, which acquire the virus during a blood meal. Here, by mutagenesis, we found a major role of the N-glycosylation of flavivirus E protein in its transmission circle, facilitating its survival against the vector immune system during invasion of the mosquito midgut while blood feeding on the host. In spite of the extensive studies of the involvement of N-glycan modification of flavivirus E protein in virus-host interactions, we discovered its critical role in virus-vector interaction and the evolution of flavivirus. Given the deleterious effects of ZIKV on human health, this study might have a significant impact on development of novel transmission-blocking strategies.

N-glycosylation of Viral E Protein Is the Determinant for Vector Midgut Invasion by Flaviviruses