Abstract
RNA interference (RNAi) controls arbovirus infections in mosquitoes. Two different RNAi pathways are involved in antiviral responses: the PIWI-interacting RNA (piRNA) and exogenous short interfering RNA (exo-siRNA) pathways, which are characterized by the production of virus-derived small RNAs of 25–29 and 21 nucleotides, respectively. The exo-siRNA pathway is considered to be the key mosquito antiviral response mechanism. In Aedes aegypti-derived cells, Zika virus (ZIKV)-specific siRNAs were produced and loaded into the exo-siRNA pathway effector protein Argonaute 2 (Ago2); although the knockdown of Ago2 did not enhance virus replication. Enhanced ZIKV replication was observed in a Dcr2-knockout cell line suggesting that the exo-siRNA pathway is implicated in the antiviral response. Although ZIKV-specific piRNA-sized small RNAs were detected, these lacked the characteristic piRNA ping-pong signature motif and were bound to Ago3 but not Piwi5 or Piwi6. Silencing of PIWI proteins indicated that the knockdown of Ago3, Piwi5 or Piwi6 did not enhance ZIKV replication and only Piwi4 displayed antiviral activity. We also report that the expression of ZIKV capsid (C) protein amplified the replication of a reporter alphavirus; although, unlike yellow fever virus C protein, it does not inhibit the exo-siRNA pathway. Our findings elucidate ZIKV-mosquito RNAi interactions that are important for understanding its spread.
Highlights
Zika virus (ZIKV) is an arbovirus belonging to the family Flaviviridae, genus Flavivirus
ZIKV is transmitted by Aedes aegypti mosquitoes, it is important to understand virus-vector interactions
Analysis of ZIKV infection in mosquito cells indicated that two RNA interference pathways are involved during infection: the exogenous short-interferingRNA and PIWI-interactingRNA pathways
Summary
Zika virus (ZIKV) is an arbovirus belonging to the family Flaviviridae, genus Flavivirus. The ZIKV genome is a single-stranded, positive-sense RNA molecule that demonstrates typical flavivirus organization—with a single open reading frame encoding the structural and non-structural proteins, flanked by 5’ and 3’ non coding regions [1,2]. Arboviruses infect arthropod vectors and induce antiviral responses that control their replication. In Aedes aegypti mosquitoes, known to be the key vector for ZIKV transmission [8], there are two RNAi pathways associated with antiviral responses: the exogenous small interfering (si)RNA (exo-siRNA) and the PIWI-interacting (pi)RNA (piRNA) pathway. Virus RNA replication results in the synthesis of double-stranded RNA (dsRNA) replication intermediates that are cleaved into 21 nucleotide (nt) long virus-specific siRNAs (vsiRNAs) by Dicer 2 (Dcr). VsiRNAs are loaded into the Argonaute 2 (Ago2) protein, which is part of the RNA-induced silencing complex (RISC). The production of vsiRNAs has been identified in arbovirus infected mosquitoes as well as in their derived cell lines [21,22,23,24,25,26,27,28,29,30]
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