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An antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication.

ABSTRACT: Alphaviruses establish a persistent infection in arthropod vectors which is essential for the effective transmission of the virus to vertebrate hosts. The development of persistence in insects is not well understood, although it is thought to involve the innate immune response. Using a transgenic fly system expressing a self-replicating viral RNA genome analog, we have previously demonstrated antiviral roles of the Drosophila Imd (immune deficiency) and Jak-STAT innate immunity pathways in response to alphavirus replication. In the present study, comparative microarray analysis of flies harboring an alphavirus replicon and control green fluorescent protein flies identified 95 SINrep-sensitive genes. Furthermore, a subset of these genes is regulated by Rel or STAT transcription factors of the Imd and Jak-STAT pathways, respectively. We identified two antimicrobial peptide genes, attC and dptB, which are SINrep sensitive and regulated by STAT and Rel, respectively. SINrep flies heterozygous for attC had an increased viral RNA level, while knocking down dptB in SINrep flies resulted in impaired development. When injected with whole virus, the double-stranded RNA knockdowns of either attC or dptB showed a significant increase in virus titers. Our data demonstrate an antiviral response involving the Imd and Jak-STAT mediated expression of dptB and attC.

SUBMITTER: Huang Z

PROVIDER: S-EPMC3624382 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Project description:Arboviruses transmitted by mosquitoes are responsible for the death of millions of people each year. In addition to arboviruses, many insect-specific viruses (ISVs) have been discovered in mosquitoes in the last decade. ISVs, in contrast to arboviruses transmitted by mosquitoes to vertebrates, cannot replicate in vertebrate cells even when they are evolutionarily closely related to arboviruses. The alphavirus genus includes many arboviruses, although only a few ISVs have been discovered from this genus so far. Here, we investigate the interactions of a recently isolated insect-specific alphavirus, Agua Salud alphavirus (ASALV), with its mosquito host. RNA interference (RNAi) is one of the essential antiviral responses against arboviruses, although there is little knowledge on the interactions of RNAi with ISVs. Through the knockdown of transcripts of the different key RNAi pathway (small interfering RNA [siRNA], microRNA [miRNA], and P-element-induced wimpy testis [PIWI]-interacting RNA [piRNA]) proteins, we show the antiviral role of Ago2 (siRNA), Ago1 (miRNA), and Piwi4 proteins against ASALV in Aedes aegypti-derived cells. ASALV replication was increased in Dicer2 and Ago2 knockout cells, confirming the antiviral role of the siRNA pathway. In infected cells, mainly ASALV-specific siRNAs are produced, while piRNA-like small RNAs, with the characteristic nucleotide bias resulting from ping-pong amplification, are produced only in Dicer2 knockout cells. Taken together, ASALV interactions with the mosquito RNAi response differ from those of arthropod-borne alphaviruses in some aspects, although they also share some commonalities. Further research is needed to understand whether the identified differences can be generalized to other insect-specific alphaviruses. IMPORTANCE Mosquitoes are efficient vectors for many arboviruses that cause emergent infectious diseases in humans. Many insect-specific viruses (ISVs) that can infect mosquitoes but cannot infect vertebrates have been discovered in the last decade. ISVs have attracted great attention due to their potential use in mosquito or arbovirus control, by either decreasing mosquito fitness or restricting arbovirus replication and transmission to humans. However, ISV-mosquito interactions are not well understood. RNA interference (RNAi) is the most important innate immune response against many arboviruses, while it is unknown if it is antiviral against ISVs. Here, we investigate in detail the antiviral effect of the RNAi response in mosquitoes against an ISV for the first time. Using a recently isolated insect-specific alphavirus, we show that the regulation of virus replication was different from that for arthropod-borne alphaviruses despite some similarities. The differences in mosquito-virus interactions could drive the different transmission modes, which could eventually drive the evolution of arboviruses. Hence, an understanding of mosquito-ISV interactions can shed light on the ecology and evolution of both ISVs and the medically important arboviruses.

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An antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication.

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