The Aedes aegypti Domino Ortholog p400 Regulates Antiviral Exogenous Small Interfering RNA Pathway Activity and ago-2 Expression

Melanie Mcfarlane (1) , Floriane Almire (1) , Joy Kean (1) , Claire Donald (1) , Alma Mcdonald (1) , Bryan Wee (2) , Mathilde Lauréti (1) , Margus Varjak (1) , Sandra Terry (1) , Marie Vazeille (3) , Rommel J Gestuveo (1, 4) , Isabelle Dietrich (1) , Colin Loney (1) , Anna-Bella Failloux (3) , Esther Schnettler (1) , Emilie Pondeville (1) , Alain Kohl (1)

1 MRC - University of Glasgow Centre for Virus Research
2 Edin. - University of Edinburgh
3 Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors
4 UP System - University of the Philippines

Arboviruses are pathogens of humans and animals. A better understanding of the interactions between these pathogens and the arthropod vectors, such as mosquitoes, that transmit them is necessary to develop novel control measures. A major antiviral pathway in the mosquito vector is the exogenous small interfering RNA (exo-siRNA) pathway, which is induced by arbovirus-derived double-stranded RNA in infected cells. Although recent work has shown the key role played by Argonaute-2 (Ago-2) and Dicer-2 (Dcr-2) in this pathway, the regulatory mechanisms that govern these pathways have not been studied in mosquitoes. Here, we show that the Domino ortholog p400 has antiviral activity against the alphavirus Semliki Forest virus (Togaviridae) both in Aedes aegypti-derived cells and in vivo. An-tiviral activity of p400 was also demonstrated against chikungunya virus (Togaviri-dae) and Bunyamwera virus (Peribunyaviridae) but not Zika virus (Flaviviridae). p400 was found to be expressed across mosquito tissues and regulated ago-2 but not dcr-2 transcript levels in A. aegypti mosquitoes. These findings provide novel insights into the regulation of an important aedine exo-siRNA pathway effector protein, Ago-2, by the Domino ortholog p400. They add functional insights to previous observations of this protein's antiviral and RNA interference regulatory activities in Dro-sophila melanogaster. IMPORTANCE Female Aedes aegypti mosquitoes are vectors of human-infecting arthropod-borne viruses (arboviruses). In recent decades, the incidence of arthropod-borne viral infections has grown dramatically. Vector competence is influenced by many factors, including the mosquito's antiviral defenses. The exogenous small interfering RNA (siRNA) pathway is a major antiviral response restricting arboviruses in mosquitoes. While the roles of the effectors of this pathway, Argonaute-2 and Dicer-2 are well characterized, nothing is known about its regulation in mosquitoes. In this study, we demonstrate that A. aegypti p400, whose ortholog Domino in Drosophila melanogaster is a chromatin-remodeling ATPase member of the Tip60 complex, regulates siRNA pathway activity and controls ago-2 expression levels. In addition, we found p400 to have antiviral activity against different ar-boviruses. Therefore, our study provides new insights into the regulation of the antiviral response in A. aegypti mosquitoes.

Mots clés: RNA interference; ago-2; arbovirus; innate immunity; mosquito; p400

Domaines: Virologie

Melanie Mcfarlane, Floriane Almire, Joy Kean, Claire Donald, Alma Mcdonald, et al.. The Aedes aegypti Domino Ortholog p400 Regulates Antiviral Exogenous Small Interfering RNA Pathway Activity and ago-2 Expression. MSphere, 2020, 5 (2), pp.e00081-20. ⟨10.1128/mSphere.00081-20⟩. ⟨pasteur-02651768⟩