Co-infection of dengue and Zika viruses mutually enhances viral replication in the mosquito Aedes aegypti

Abstract

Background The mosquito Aedes aegypti transmits two of the most serious mosquito-borne viruses, dengue virus (DENV) and Zika virus (ZIKV), which results in significant human morbidity and mortality worldwide. The quickly shifting landscapes of DENV and ZIKV endemicity worldwide raise concerns that their co-circulation through the Ae. aegypti mosquito vector could greatly exacerbate the disease burden in humans. Recent reports have indicated an increase in the number of co-infection cases in expanding co-endemic regions; however, the impact of co-infection on viral infection and the detailed molecular mechanisms remain to be defined. Methods C6/36 (Aedes albopictus) cells were cultured in Dulbecco's modified Eagle medium/Mitsuhashi and Maramorosch Insect Medium (DMEM/MM) (1:1) containing 2% heat-inactivated fetal bovine serum and 1× penicillin/streptomycin solution. For virus propagation, the cells were infected with either DENV serotype 2 (DENV2) strain 16681 or ZIKV isolate Thailand/1610acTw (MF692778.1). Mosquitoes (Ae. aegypti UGAL [University of Georgia Laboratory]/Rockefeller strain) were orally infected with DENV2 and ZIKV through infectious blood-feeding. Results We first examined viral replication activity in cells infected simultaneously, or sequentially, with DENV and ZIKV, and found interspecies binding of viral genomic transcripts to the non-structural protein 5 (NS5). When we challenged Ae. aegypti mosquitos with both DENV2 and ZIKV sequentially to probe similar interactions, virus production and vector susceptibility to infection were significantly enhanced. Conclusions Our results suggest that DENV2 and ZIKV simultaneously establishing infection in the Ae. aegypti mosquito vector may augment one another during replication. The data also implicate the homologous NS5 protein as a key intersection between the flaviviruses in co-infection, highlighting it as a potential target for vector control.

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

“…Further investigations are warranted to elucidate the intricate interplay between these two viruses. A recent study also conducted DENV (serotype 2) and ZIKV sequential coinfection in A. aegypti [88]. One of their findings is consistent with our own observations as ZIKV-infected A. aegypti strongly suppressed the replication of subsequently infected DENV (group ZIKV !…”

“…A recent study also conducted DENV (serotype 2) and ZIKV sequential coinfection in A . aegypti [ 88 ]. One of their findings is consistent with our own observations as ZIKV-infected A .…”

“…It is noticeable that in arbovirus sequential coinfection, prior virus titer might play a critical role in interfering with later virus development [ 88 ]. In this study, the initial viruses used for thoracic inoculation were at a similar dose (DENV: 10 5.5 copies/ml and ZIKV: 10 5.4 copies/ml), which could minimize the density-dependent competitive suppression of the second virus.…”

Simultaneous Dengue and Chikungunya Coinfection in Endemic Area in Brazil: Clinical Presentation and Implications for Public Health

“…Peculiarly, Aedes aegypti mosquitoes have been extensively studied, revealing that this mosquito species can harbor hosts and vectors for both viruses in vitro settings [ 16 , 17 ]. Lin and colleagues (2023) further demonstrated that simultaneous infection with DENV and Zika virus in Aedes aegypti could intensify viral replication within the mosquito [ 18 ]. This enhanced replication capacity, alongside the mosquito’s ability to transmit multiple viruses, raises critical questions regarding the potential for human infection resulting from successive exposures to mosquitoes carrying DENV, CHIKV, or both.…”

A tangled threesome: understanding arbovirus infection in Aedes spp. and the effect of the mosquito microbiota

“…It is possible that co-infection with ISV could also facilitate subsequent arbovirus infections by reducing the activity of iRNA with their sfRNA, this could also help to evade response through vDNA. On the other hand experimental co-infections with two arbovirus (DENV2 and ZIKV) have shown mutual enhancement, mediated by the non-structural protein NS5 (Lin et al, 2023 ).…”