Project Description
Public­ations

TP13: Dynamics of anti-viral immunity against viral infection of the liver

Using sophisticated in vivo HBV infection models, we are able to trace adaptive immunity in real-time. With this, we have demonstrated that innate immunity stimulation is able to overcome dysfunctional CD8 T cells during chronic HBV infection and to restore anti-HBV immunity leading to clearance of the infection. Using single cell RNA sequencing, we identified a Tcf7+ progenitor cell population within the liver. Stimulation of these progenitor cells in a type I interferon dependent manner, leads to their proliferation and differentiation into effector cells eliminating HBV replicating hepatocytes. We now study in detail the intrahepatic localisation of those Tcf7+ progenitor cells and their functional properties.
Brugger M, Laschinger M, Lampl S, Schneider A, Manske K, Esfandyari D, Huser N, Hartmann D, Steiger K, Engelhardt S, Wohlleber D, Knolle PA. (2022) High precision-cut liver slice model to study cell-autonomous antiviral defense of hepatocytes within their microenvironment. JHEP Rep 4, 100465. doi:10.1016/j.jhepr.2022.100465.
Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, Manske K, Sperl LE, Klager S, Kuster B, Wettmarshausen J, Muller C, Laschinger M, Hartmann D, Huser N, Perocchi F, Schmitt-Kopplin P, Hagn F, Zender L, Hornung V, Borner C, Pichlmair A, Kashkar H, Klingenspor M, Prinz M, Schreiner S, Conrad M, Jost PJ, Zischka H, Steiger K, Kronke M, Zehn D, Protzer U, Heikenwalder M, Knolle P.A., Wohlleber, D. (2020) Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. J Hepatol 73, 1347-1359. doi:10.1016/j.jhep.2020.06.026.
Manske K, Schneider A, Ko C, Knolle PA, Steiger K, Protzer U, Wohlleber D. (2021) In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity. Viruses 13. doi:10.3390/v13112273.
Winkler F, Hipp AV, Ramirez C, Martin B, Villa M, Neuwirt E, Gorka O, Aerssens J, Johansson SE, Rana N, Llewellyn-Lacey S, Price DA, Panning M, Gross O, Pearce EL, Hermann CM, Schumann K, Hannibal L, Neumann-Haefelin C, Boettler T, Knolle P, Hofmann M, Wohlleber D, Thimme R, Bengsch B. (2023) Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8(+) T cells. Gut 72, 1971-1984. doi:10.1136/gutjnl-2022-328734.
10. Manske K, Kallin N, Konig V, Schneider A, Kurz S, Bosch M, Welz M, Cheng RL, Bengsch B, Steiger K, Protzer U, Thimme R, Knolle PA, Wohlleber D. (2018) Outcome of anti-viral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes. Hepatology. doi:10.1002/hep.30080.
Wohlleber D, Kashkar H, Gartner K, Frings MK, Odenthal M, Hegenbarth S, Borner C, Arnold B, Hammerling G, Nieswandt B, van Rooijen N, Limmer A, Cederbrant K, Heikenwalder M, Pasparakis M, Protzer U, Dienes HP, Kurts C, Kronke M, Knolle PA. (2012) TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep 2, 478-487. doi:10.1016/j.celrep.2012.08.001.
Schneider A, Kurz S, Manske K, Janas M, Heikenwalder M, Misgeld T, Aichler M, Weissmann SF, Zischka H, Knolle P, Wohlleber D. (2019) Single organelle analysis to characterize mitochondrial function and crosstalk during viral infection. Sci Rep 9, 8492. doi:10.1038/s41598-019-44922-9.
Esser K, Cheng X, Wettengel JM, Lucifora J, Hansen-Palmus L, Austen K, Roca Suarez AA, Heintz S, Testoni B, Nebioglu F, Pham MT, Yang S, Zernecke A, Wohlleber D, Ringelhan M, Broxtermann M, Hartmann D, Huser N, Mergner J, Pichlmair A, Thasler WE, Heikenwalder M, Gasteiger G, Blutke A, Walch A, Knolle PA, Bartenschlager R, Protzer U. (2023) Hepatitis B Virus Targets Lipid Transport Pathways to Infect Hepatocytes. Cell Mol Gastroenterol Hepatol 16, 201-221. doi:10.1016/j.jcmgh.2023.03.011.
Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Youngblood B, Zehn D. (2019) TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265-269. doi:10.1038/s41586-019-1326-9.