PhD defense: Karim MOUZANNAR
Date / Heure
Date(s) - 15/06/2018
Toute la journée
salle des Thèses Chantal Rabourdin-Combes
PhD defence: Karim MOUZANNAR , team « Cell biology of viral infections »,Friday june 15th in salle des thèses (ENS de Lyon-Site Monod) at 14h00.
« Identification of the nuclear receptor for bile acids FXR alpha as a proviral factor for hepatitis B virus. »
Hepatitis B virus (HBV) infection is a major global health problem with more than 257 million chronic carriers worldwide that remain at significant risk for developing cirrhosis and/or hepatocellular carcinoma. The natural history of infection is very different depending on the age at which the infection is contracted. Whereas in adults most HBV infections spontaneously resolve, in infants and young children they usually result in chronic infection. cccDNA is the molecular form of viral persistence in infected hepatocytes and serves as a transcription template for all viral RNAs. The viral protein HBx plays a crucial role in the recruitment of epigenetic factors to the cccDNA and promotes its transcriptional activity. Currently, interferon and nucleot(s)ide analogues are the first-line agents in the treatment of chronic hepatitis B without allowing eradication of cccDNA and their interruption are almost always followed by a reactivation of the replication of the virus. New therapeutic molecules targeting cccDNA are therefore needed to hope for a functional cure in chronically infected patients.
HBV infection and bile acid (BA) metabolism are tightly linked. Therefore, our team has previously shown that the bile acid nuclear receptor, the farnesoid X receptor alpha (FXRa) bind to two response elements present in the Enhancer II – Core promoter region of HBV genome and modulate its transcriptional activity. Moreover, HBV and BA compete for the same entry receptor of hepatocytes NTCP and modify BA cell concentration with consequences on the function and expression of FXRa. Finally, HBx interacts with FXRa and modify its activity.
During my PhD. we have first identified a reciprocal regulation between HBV replication and FXRa. Second, we have showed in vitro, in HepaRG differentiated cells and in primary human hepatocytes, that FXRa is a proviral factor for HBV and that FXRa agonists inhibit the expression of all HBV markers in a dependent or independent manner of the viral protein HBx. Finally, in an in vivo model of C3H/HeN mice transduced with a recombinant AAV2/8-HBV vector, we obtained the inhibitory effect of FXRa agonists but only in adult and not in young mice. Considering the evolution of the gut flora with age and its importance in the metabolism of BA, these results suggest that the high rate of chronic progression in young children might be related to the immaturity of BA metabolism.
The identification of a link between BA metabolism, gut microbiome composition and evolution of HBV infection will represent a big step toward the understanding of HBV natural history. Moreover, the identification of FXRa as a proviral factor for HBV and the capacity of FXRa ligands to modulate the transcriptional activity of cccDNA suggest that FXRa ligands might represent a new class of molecules with the aim to obtain functional cure for HBV infected patients.
ROINGEARD Philippe PU-PH Université de Tours Rapporteur
SOUSSAN Patrick MCU-PH Université Paris VI Rapporteur
INCHAUSPÉ Geneviève DR Transgene SA Examinatrice
MARGOTTIN-GOGUET Florence DR INSERM Paris Examinatrice
RAMIÈRE Christophe MCU-PH Université Lyon I Examinateur
ANDRÉ Patrice PU-PH Université Lyon I Directeur de thèse