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

ZIKActin Project

Molecular analysis of the innate responses against Zika virus infection

Coordinator : Anja Böckmann (MMSB) - Ecofect Partners: Marlène Dreux (CIRI) & Bastien Boussau (LBBE) - External partners : Saw See Hong (EPHE) & Colette Dehay (SBRI)

Zika virus (ZIKV) has recently been associated with neurological diseases, thus representing an important public-health emergency. The current spread in the Americas and the tropical regions reinforces the urgency to understand ZIKV biology for the design of therapeutics and vaccines. The first recent in vivo study in mouse models revealed that the host antiviral response leading to interferon (IFN) production is pivotal both for the control of ZIKV replication, the neurological disease and in utero transmission, in agreement with the inhibition of in vitro ZIKV replication by IFNs.

The ZIKActin project has for ojectives to:
• Determine, at the cellular level, the modulations of the host responses by ZIKV and their impact on viral spread and on the biology of neuronal progenitors, using neuronal stem cells, a validated in vitro model for neuronal differentiation and ZIKV infection.
• Conduct an unbiased novel evolutionary experiment that will reveal the genetic interactions with the host defense responses in ZIKV genome and the viral escape from the antiviral responses. We will further evaluate how the selective constraints uncovered during experimental evolution match the wider-scale natural selective pressure computed from available sequences sampled in the wild.
• Determine by in silico and biophysical approaches how adaptation at the sites identified in the ZIKV genome affects ZIKV protein structure and function. This will enable a better understanding of the structural basis of the interplay between ZIKV and the host sensing.

Our project will delineate the genetic interactions of ZIKV with the host responses, by combining new methods of high-throughput sequencing and bioinformatics and by mapping the identified key viral determinants on the protein structures/structural models. Additionally, our experimental evolution strategy will entail conceptual insights in molecular evolution and reveal potential routes towards viral escape. It will thus provide guidelines for therapeutic design. This is particularly important in the current context of the ZIKV epidemics, but also on a longer run, to anticipate future viral epidemics of this family of viruses and other neurotropic viruses where a deeper understanding of viral infection is central.

Coordinator : Anja Böckmann, team "RMN du solide des protéines" (MMSB)
Ecofect partners : Marlène Dreux, team "Traffic Vésiculaire, Réponse Innée et Virus" (CIRI) & Bastien Bousseau, team "Bioinformatique, Phylogénie et Génomique Evolutive" (LBBE).
External partners : Saw See Hong (EPHE) & Colette Dehay (SBRI)
Project duration : 3 years
Financing :
PhD and postoctoral fellowships and consumable money
PhD fellow:
Guillaume David
Post-doctoral fellow:
Sara Munoz Gonzalez