Control of dengue virus in the midgut of Aedes aegypti by ectopic expression of the dsRNA-binding protein Loqs2

Dengue virus (DENV) is an arbovirus transmitted to humans by Aedes mosquitoes 1 . In the insect vector, the small interfering RNA (siRNA) pathway is an important antiviral mechanism against DENV 2 – 5 . However, it remains unclear when and where the siRNA pathway acts during the virus cycle. Here, w...

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Published in:	Nature microbiology Vol. 3; no. 12; pp. 1385 - 1393
Main Authors:	Olmo, Roenick P., Ferreira, Alvaro G. A., Izidoro-Toledo, Tatiane C., Aguiar, Eric R. G. R., de Faria, Isaque J. S., de Souza, Kátia P. R., Osório, Kátia P., Kuhn, Lauriane, Hammann, Philippe, de Andrade, Elisa G., Todjro, Yaovi Mathias, Rocha, Marcele N., Leite, Thiago H. J. F., Amadou, Siad C. G., Armache, Juliana N., Paro, Simona, de Oliveira, Caroline D., Carvalho, Fabiano D., Moreira, Luciano A., Marois, Eric, Imler, Jean-Luc, Marques, João T.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2018 Nature Publishing Group
Subjects:	14/63 38/77 38/91 42/44 42/89 45 631/250/262 631/326/596/1413 631/326/596/2553 64 82 82/58 Aedes Aedes - genetics Aedes - metabolism Aedes - virology Aedes aegypti Animal biology Animals Animals, Genetically Modified Antiviral Agents - metabolism Antiviral Agents - pharmacology Biomedical and Life Sciences Carrier Proteins - genetics Carrier Proteins - metabolism Dengue - virology Dengue fever Dengue Virus - drug effects Dengue Virus - genetics Dengue Virus - metabolism Dengue Virus - pathogenicity Disease transmission DNA Replication Double-stranded RNA Ectopic expression Ectopic Gene Expression Female Gastrointestinal Tract - virology Gene Silencing Host-Pathogen Interactions Immunology Infectious Diseases Innate immunity Invertebrate Zoology Letter Life Sciences Medical Microbiology Microbiology Midgut Mosquito Vectors - virology Parasitology Replication RNA, Double-Stranded - metabolism RNA, Small Interfering - metabolism RNA, Viral - metabolism RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism RNA-Binding Proteins - pharmacology RNA-mediated interference siRNA Virology Virus Replication Zika Virus - metabolism
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Summary:	Dengue virus (DENV) is an arbovirus transmitted to humans by Aedes mosquitoes 1 . In the insect vector, the small interfering RNA (siRNA) pathway is an important antiviral mechanism against DENV 2 – 5 . However, it remains unclear when and where the siRNA pathway acts during the virus cycle. Here, we show that the siRNA pathway fails to efficiently silence DENV in the midgut of Aedes aegypti although it is essential to restrict systemic replication. Accumulation of DENV-derived siRNAs in the midgut reveals that impaired silencing results from a defect downstream of small RNA biogenesis. Notably, silencing triggered by endogenous and exogenous dsRNAs remained effective in the midgut where known components of the siRNA pathway, including the double-stranded RNA (dsRNA)-binding proteins Loquacious and r2d2, had normal expression levels. We identified an Aedes -specific paralogue of loquacious and r2d2 , hereafter named loqs2 , which is not expressed in the midgut. Loqs2 interacts with Loquacious and r2d2 and is required to control systemic replication of DENV and also Zika virus. Furthermore, ectopic expression of Loqs2 in the midgut of transgenic mosquitoes is sufficient to restrict DENV replication and dissemination. Together, our data reveal a mechanism of tissue-specific regulation of the mosquito siRNA pathway controlled by Loqs2. Although essential to restrict systemic replication, the small interfering RNA pathway fails to efficiently silence dengue virus in the midgut of Aedes aegypti in the absence of ectopic expression of the double-stranded RNA-binding protein Loqs2.
ISSN:	2058-5276 2058-5276
DOI:	10.1038/s41564-018-0268-6