Biased virus transmission following sequential coinfection of Aedes aegypti with dengue and Zika viruses.

Background: Mosquito-borne arboviruses are expanding their territory and elevating their infection prevalence due to the rapid climate change, urbanization, and increased international travel and global trade. Various significant arboviruses, including the dengue virus, Zika virus, Chikungunya virus, and yellow fever virus, are all reliant on the same primary vector, Aedes aegypti. Consequently, the occurrence of arbovirus coinfection in mosquitoes is anticipated. Arbovirus coinfection in mosquitoes has two patterns: simultaneous and sequential. Numerous studies have demonstrated that simultaneous coinfection of arboviruses in mosquitoes is unlikely to exert mutual developmental influence on these viruses. However, the viruses' interplay within a mosquito after the sequential coinfection seems intricated and not well understood. Methodology/principal findings: We conducted experiments aimed at examining the phenomenon of arbovirus sequential coinfection in both mosquito cell line (C6/36) and A. aegypti, specifically focusing on dengue virus (DENV, serotype 2) and Zika virus (ZIKV). We firstly observed that DENV and ZIKV can sequentially infect mosquito C6/36 cell line, but the replication level of the subsequently infected ZIKV was significantly suppressed. Similarly, A. aegypti mosquitoes can be sequentially coinfected by these two arboviruses, regardless of the order of virus exposure. However, the replication, dissemination, and the transmission potential of the secondary virus were significantly inhibited. We preliminarily explored the underlying mechanisms, revealing that arbovirus-infected mosquitoes exhibited activated innate immunity, disrupted lipid metabolism, and enhanced RNAi pathway, leading to reduced susceptibility to the secondary arbovirus infections. Conclusions/significance: Our findings suggest that, in contrast to simultaneous arbovirus coinfection in mosquitoes that can promote the transmission and co-circulation of these viruses, sequential coinfection appears to have limited influence on arbovirus transmission dynamics. However, it is important to note that more experimental investigations are needed to refine and expand upon this conclusion. Author summary: Arboviruses coinfection in mosquitoes can occur either simultaneously or sequentially. Simultaneous coinfection of arboviruses in mosquitoes is unlikely to exert mutual developmental influence on these viruses, resulting in a single mosquito bite may transmit multiple arboviruses to humans, thereby facilitating the spread of these pathogens. However, the interplay between viruses within a mosquito after the sequential coinfection is intricated and not well understood. We present results from DENV (serotype 2) and ZIKV sequential coinfection both in mosquito cell line (C6/36) and Aedes aegypti. Our results demonstrated that both mosquito cells and adult mosquitoes could be sequentially coinfected, but prior infection with one arbovirus significantly reduced susceptibility to a secondary arbovirus infection. Moreover, upon sequential coinfection with DENV and ZIKV through oral feeding, the transmission potential of A. aegypti for the ZIKV was aborted. We preliminarily explored the underlying mechanism of this phenomenon and observed that arbovirus-infected mosquitoes exhibited activated innate immunity, disrupted lipid metabolism, and enhanced RNAi pathway, all of which contributed to the reduced susceptibility to the secondary arbovirus infections. In the epidemiology of mosquito borne diseases, our findings indicates that, in contrast to simultaneous arbovirus coinfection in mosquitoes that can promote the transmission and co-circulation of these viruses, sequential coinfection appears to have limited influence on arbovirus transmission dynamics. [ABSTRACT FROM AUTHOR]