Abstract
Dengue virus (DENV) relies on host factors to complete its life cycle in its mosquito host for subsequent transmission to humans. DENV first establishes infection in the midgut of Aedes aegypti and spreads to various mosquito organs for lifelong infection. Curiously, studies have shown that infectious DENV titers peak and decrease thereafter in the midgut despite relatively stable viral genome levels. However, the mechanisms that regulate this decoupling of infectious virion production from viral RNA replication have never been determined. We show here that the ubiquitin proteasome pathway (UPP) plays an important role in regulating infectious DENV production. Using RNA interference studies, we show in vivo that knockdown of selected UPP components reduced infectious virus production without altering viral RNA replication in the midgut. Furthermore, this decoupling effect could also be observed after RNAi knockdown in the head/thorax of the mosquito, which otherwise showed direct correlation between infectious DENV titer and viral RNA levels. The dependence on the UPP for successful DENV production is further reinforced by the observed up-regulation of key UPP molecules upon DENV infection that overcome the relatively low expression of these genes after a blood meal. Collectively, our findings indicate an important role for the UPP in regulating DENV production in the mosquito vector.
Highlights
Dengue is the most important arthropod-borne viral disease globally
Blocking host factors required for Dengue virus (DENV) replication in mosquitoes may serve as an effective anti-transmission strategy
We have recently observed that the ubiquitin proteasome pathway (UPP) plays a critical role in regulating DENV egress from infected cells, but how the UPP contributes to DENV life cycle in mosquitoes remain ill
Summary
Dengue is the most important arthropod-borne viral disease globally. Dengue virus (DENV) propagates itself through cyclic human-mosquito-human transmission with Aedes aegypti (Ae. aegypti) being the principal vector [1]. The global distribution of the four antigenically distinct DENV (DENV-1, DENV-2, DENV-3 and DENV-4) along with their mosquito vectors causes an estimated 390 million infections annually [2]. Another 3 billion people that live in or travel to the tropics are at constant risk of infection with any of the four DENV serotypes [2]. The effectiveness of vector control alone in preventing DENV transmission has had mixed success. While the eradication effort of Ae. aegypti by Pan American Health Organization (PAHO) in South America, and the vector control programs by Cuba and Singapore have had remarkable outcomes in reducing dengue incidence, their effectiveness have been temporary for reasons previously reviewed [5,6,7,8]. Better tools to either reduce vector population density or their vector competence are urgently needed to augment current preventive efforts
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