Flaviviridae Infection of Brain and Liver Organotypic Cultures – FlavIBLOC

Flaviviridae such as Dengue virus (DenV), West Nile fever virus (WNV) and Yellow fever virus (YFV) are known to infect liver and brain to various degree leading to either hepatitis and/or encephalitis. Early steps and organs responses to the infection are very poorly documented due to lack of efficient tools. We have developed and standardized highly valuable hamster organotypic cultures of brain and liver allowing for the first time to decipher in real time the virus host interaction directly in organs. While WNV seems to preferentially target the brain, most of YFV strains are only hepatotropic but still conserve the ability to trigger distant encephalitis. Data about DenV interaction with the two organs remains poorly documented. We expect our highly valuable ex vivo models of brain and liver organotypic cultures, especially developed for studying physiopathology of viral infections at the organ scale, able to fil such lack. The aim of FLavIBLOC is to analyze, for the first time in our new integrated ex-vivo culture system, the detailed cellular tropism, dynamic of infection, metabolic and innate immune responses involved during liver and brain infection by these three viruses. Finally, we will test interference with the development of liver and neurological diseases using metabolic modulators. This project will identify the key pathophysiological mechanisms of either viral-induced hepatitis and/or encephalitis. Since there is no effective treatment for humans, our proposal will also provide informations to: i) better anticipate severe cases of these diseases by identifying early biomarkers of hepatitis and encephalitis, and ii) identify potential effective molecules targeting the host for therapeutic approaches.