Download Hepatitis B Virus induces innate immune response UPOn COntact

HEPATITIS B VIRUS INDUCES INNATE IMMUNE RESPONSE UPON CONTACT WITH HUMAN LIVER MACROPHAGES
AND ENDOTHELIAL CELLS, BUT NOT HEPATOCYTES
M. Broxtermann1, K. Esser1, S. Gillen4, S. Arzberger1, M. Hösel2,3, J. Lucifora1 & U. Protzer1
1
Institute of Virology, Technische Universität München / Helmholtz Zentrum München 2 Center for Molecular Medicine Cologne
(CMMK) 3 Department of Internal Medicine I 4 Dept. of Surgery, Klinikum rechts der Isar, Munich
The role of adaptive immune response to HBV infection is widely studied but innate immune responses are poorly understood.
The liver is not only a target organ of the immune response but also plays an important role in inducing and turning immunity. It
consists of parenchymal hepatocytes and of non-parenchymal cells. Productive HBV infection is restricted to hepatocytes but
the virus is also in contact to non-parenchymal liver cells. The aim of this work was to address the ability of HBV to trigger an
innate immune response upon contact with the different liver cells.
>95% pure populations of primary human hepatocytes (PHH), peripheral and liver macrophages (Kupffer cell, KC) and liver
sinusoidal endothelial cells (LSEC) were established. Primary liver cell populations were identified by receptor mediated
phagocytosis and expression of typical markers. Primary human macrophages were differentiated from isolated monocytes in
vitro. Murine macrophages were differentiated from bone marrow cells. Infectious HBV inocula were concentrated from the
medium of HBV replicating cell line HepG2.2.15. As a mock control, concentrated supernatant from HepG2 cells was used.
We found that HBV induced proinflammatory cytokines like IL-6, IL-8 and TNFα in KC, LSEC and monocyte derived
macrophages within a few hours post inoculation, but not in PHH or murine macrophages. The same held true for
adenoassociated virus (AAV) particles used as a control. The viruses activated NFκB, but did neither activate the inflammasome
nor induce antiviral IFN type I. IL-6 induction persisted after UV irradiation but was reduced by Ca2+ depletion and chemical
inhibition of phagocytosis. Our data show that HBV particles or antigens trigger an innate immune response that is independent
of a productive infection, most likely via a pattern recognition receptor that involves NFκB but does not activate IRFs or the
inflammasome.