Dissection moléculaire du parasitage des fonctions cellulaires par les virus de la dengue et Zika et développement de nouvelles classes d'antiflaviviraux

 

Laurent Chatel-Chaix

Institut national de la recherche scientifique [INRS]

 

Domaine : maladies infectieuses et immunitaires

Programme Chercheurs-boursiers - Junior 2

Concours 2018-2019

Infections with flaviviruses constitute a major global public health concern worldwide. Notably, dengue virus (DENV) causes the most prevalent mosquito-borne viral disease with estimated 400 million infections and is potentially lethal.

More recently, the outbreak in the Americas of Zika virus (ZIKV), closely related to DENV, brought a lot of attention notably because infection of pregnant women can lead to congenital transmission and eventually to microcephaly in the infant in addition to other neurological complications.

Unfortunately, no antiviral therapies treating these diseases are currently available. Antiviral drug development remains challenging because very little is known about the molecular mechanisms governing the replication of DENV and ZIKV within infected cells. Following viral entry into the cell, viral proteins remodel cellular organelles such as the endoplasmic reticulum and the mitochondria to create an intracellular environment which is favorable to viral replication. Intuitively, this remodeling involves the activation of proviral processes and the inhibition of defense mechanisms.

Our research program aims at identifying such cellular processes reprogrammed by DENV and ZIKV to their advantage as well as at molecularly dissecting the mechanisms regulating them. A special focus will be given to the intracellular fate of the viral RNA genome as well as mitochondria, the powerhouse of the cell and their functions in programmed cell death, intracellular calcium homeostasis and metabolism. Finally, the developed tools will be exploited to engineer novel small molecules inhibitors of DENV and ZIKV replication.

Ultimately, this project may pave the way to the identification novel drug targets for therapeutic treatments of both dengue and Zika fevers and associated complications.