Published on December 14, 2018 | Updated on December 14, 2018

ERMIT Project

Endogenous Retroviruses and iMmunITy

Co-leaders : Marie Fablet (LBBE) & Maxime Ratinier (ENS)

Endogenous retroviruses (ERVs) are viral sequences integrated into the host genome, which are relics of ancient infections. Genomic integration may lead to deleterious mutations. Natural selection has favored the establishment of control mechanisms allowing to circumvent their negative impact. In particular, RNA interference (RNAi) pathways via piRNAs (PIWI interacting small interfering RNAs) are involved in ERV transcript repression. These ERV control pathways act as an immunity mechanism at the genomic level. Moreover, such RNAi pathways have been also described during the host antiviral response and several pieces of evidence suggest that these RNA interference pathways controlling ERV and viral replication may crosstalk. For instance, in mosquitoes that are experimentally infected with an arthropod-borne virus (arbovirus) such as the Dengue virus, virus-derived piRNAs are produced during infection and participate to the anti-viral immunity. Moreover, the piRNA pathway can also limit the viral replication of arboviruses in insects and allow the persistent infection of the host without deleterious effect —a key parameter of vector competence.
In recent years, we have witnessed emergences of infectious diseases that have raised great concern in public health as well as in veterinary field. Some of them are caused by arboviruses, which include, among others, members of the Phlebovirus genera of the Bunyaviridae family, such as Toscana virus (TOSV) and Rift Valley Fever Virus (RVFV). RVFV is responsible for severe zoonotic infectious diseases and displays a large spectrum of competent arthropod vectors. TOSV is transmitted by sand flies of Psychodidae family. In the Mediterranean area, TOSV is the most important aetiological agent of human central nervous system (CNS) infections during the summer. Most interestingly, it was shown that TOSV can be vertically (transovarially) transmitted in its insect host. Hence, we aim to explore the interplay between the host response to arbovirus infections and ERV genomic immunity mediated through RNA interference in insects. Two hypotheses may be proposed: (i) either a high abundance/activity of ERVs primes the small RNA immune response resulting in an antiviral state of the insect and thus reducing or preventing virus replication (ii) or a trade-off exists between the control of ERVs integrated within the genome and the response to virus infections, therefore modulating the insect’s ability to replicate efficiently the virus. To discriminate between these two hypotheses, we will decipher the RNAi interference response during virus infection in insects.
We propose to use a powerful system of wild-type strains of Drosophila simulans and Drosophila melanogaster, for which the “Transposable Elements, Evolution, Populations” team has already identified distinct RNAi responses depending on the ERV abundance in the genome and their transcriptional activities. In parallel, we will also use a laboratory line of D. melanogaster (named Dmts), which increases expression of ERVs in the ovaries after a temperature shift from 23°C to 29°C.
The identification of factors that are modulating/determining the response of the insect to viral infections (and hence, potentially the vector competence of arbovirus in their natural host) is critical to facilitate and foreseen the design of new strategies and therapeutics to tackle and/or prevent the virus infections and their associated diseases. The issue of the way insects deal with arbovirus infections according to their ERV load is a matter of great concern considering the huge impact arboviruses have on human health. This project will provide an integrative view of the RNAi response and in particular of the impact of genomic ERVs on this anti-viral mechanism during arbovirus infections in insect. Considering the natural variability of ERV copy numbers in the insect genomes, our results may also be relevant at the level of populations (that are complex and diverse).

Co-leaders : Marie Fablet, team "Eléments transposables, Evolution, Populations" (LBBE) & Maxime Ratinier, team "Infections virales et pathologies comparées" (ENS).
Project duration : 3 years
Financing :
PhD fellowship & consumable money
PhD fellow : Marlène Roy