TP02A: Modelling enteric hepatotropic virus infection: impact of the enteric stage on the outcome of liver infectionHepatitis A virus (HAV) and hepatitis E virus (HEV) are the leading causes of acute viral hepatitis in developing countries with poor sanitary conditions. Historically, as both viruses have been thought to only cause acute disease, interest in studying them has been low.
Stephanie Margarete Münchau, Rosalie Deutsch, Thomas Hielscher, Nora Heber, Beate Niesler, Megan Lynn Stanifer, Steeve Boulant. Hypoxic environment promotes barrier formation in human intestinal epithelial cells through regulation of miRNA-320a expression. (in press) MCB 2019Pervolaraki K, Rastgou Talemi S, Albrecht D, Bormann F, Bamford C, Mendoza JL, Garcia KC, McLauchlan J, Höfer T, Stanifer ML, Boulant S. Differential induction of in-terferon stimulated genes between type I and type III interferons is independent of inter-feron receptor abundance. PLoS Pathog. 2018Stanifer, M. L., Kischnick, C., Rippert, A., Albrecht, D., and Boulant, S. (2017) Reovirus inhibits interferon production by sequestering IRF3 into viral factories. Sci. Rep. 7, 10873Pervolaraki, K., Stanifer, M. L., Münchau, S., Renn, L. A., Albrecht, D., Kurzhals, S., Senís, E., Grimm, D., Schröder-Braunstein, J., Rabin, R. L., and Boulant, S. (2017) Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut. Front Immunol. 8, 459Stanifer, M. L., Rippert, A., Kazakov, A., Willemsen, J., Bucher, D., Bender, S., Bartenschlager, R., Binder, M., and Boulant, S. (2016) Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF-β dependent pro-survival signaling. Cell. Microbiol. 18, 1831–1845Dao Thi VL, Debing Y, Wu X, Rice CM, Neyts J, Moradpour D*, and Gouttenoire J* (2016) Sofosbuvir inhibits Hepatitis E virus replication in vitro and results in an additive effect when combined with ribavirin. Gastroenterology. 150:82-85Wu X*, Dao Thi VL*, Liu P, Takacs CN, Xiang K, Andrus L, Gouttenoire J, Moradpour D, and Rice CM (2018). Pan-Genotype Hepatitis E Virus Replication in Stem Cell-Derived Hepatocellular Systems. Gastroenterology. 154(3):663-674.e7Wu X, Dao Thi VL, Huang Y, Billerbeck E, Saha D, Hoffmann HH, Wang Y, Vale Silva LA, Sarbanes S, Sun T, Andrus L, Quirk C, MacDonald MR, Schneider WM, An X, Rosenberg BR, and Rice CM (2018). Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell. 172(3):423-438.e25Dao Thi VL, Wu X, and Rice CM (2018). Stem Cell-Derived Culture Models of Hepatitis E Virus Infection. Cold Spring Harb Perspect Med. pii: a03179Gouttenoire J, Pollán A, Abrami L, Oechslin N, Mauron J, Matter M1, Oppliger J, Szkolnicka D, Dao Thi VL, van der Goot FG, Moradpour D. (2018) Palmitoylation mediates membrane association of hepatitis E virus ORF3 protein and is required for infectious particle secretion PLoS Pathog. 2018 Dec 10;14(12):e1007471. doi: 10.1371/journal.ppat.1007471
As a result, the immune responses generated by HAV and HEV and the pathogenesis of infection remain poorly understood. Despite the absence of viral glycoproteins, both viruses can acquire a cell host-derived lipid envelope during virus morphogenesis, allowing the virus to bud in a noncytolytic fashion. This quasi-envelope protects HAV and HEV from neutralizing antibodies and facilitates systemic spread within the host, whereas the nonenveloped/naked virions, which are shedded in feces, are very stable and allow for epidemic transmission. Both viruses then spread fecal-orally in humans through contaminated water and food. In addition, HEV infection can be zoonotically transmitted through ingestion of contaminated meat. The intestinal epithelium is the first physical barrier that HAV and HEV must cross to enter the bloodstream and gain access to hepatocytes, their major replication site. To date, very little is known about the lifecycle of HAV and HEV in intestinal epithelial cells and it is unclear whether the enteric phase of these viruses can influence the onset of infection and viral replication in the liver. Within this associated project we aim at addressing how the enteric phase of HAV and HEV lifecycle may impact virus replication and spread in the liver and ultimately study whether this contributes to the acute nature of HAV and HEV infections.
Mechanisms of antiviral therapy-induced virus-specific CD8+ T cell restoration in chronic viral hepatitis
Viral escape from dominant virus-specific CD8+ T cell responses and restoration strategies in HBV mono- and HBV/HDV co-infection
Generation of effective antiviral CD4 T cell immunity in viral hepatitis and its association to unique signatures of transcription factors
Lymphotoxin β receptor signalling-dependent control of virus clearance in chronic hepatitis B virus and hepatitis C virus infections
Dissecting NK cell-mediated immune responses against hepatitis B virus and hepatitis C virus infection
Mechanisms of interferon induction by hepatitis D virus and impact of chronic innate immune activation on antiviral immunity
Determinants of success and failure to control hepatitis C virus infection by the interferon system
Global effects on host cell signalling by continuous stimulation of innate antiviral responses in persistent viral infections
Role of the host stress response in the establishment of viral persistence: comparative analysis of HCV and HAV infection
Unravelling the role of DNA repair in the formation of the hepatitis B virus cccDNA persistence reservoir
Contribution of innate immune responses to persistence versus clearance of hepatitis C and hepatitis A virus infections
Combinatorial knock-down/knock-out strategies to reconstitute anti-HBV immune responses and to eliminate persisting HBV cccDNA