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PLoS Pathog. 2018 Aug 3;14(8):e1007235. doi: 10.1371/journal.ppat.1007235. eCollection 2018 Aug.

Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice.

Author information

1
Institute for Radiology, Hannover Medical School, Hannover, Germany.
2
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, Hannover, Germany.
3
Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
4
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
5
Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
6
Helmholtz Centre for Infection Research, Genome Analytics Research Group, Braunschweig, Germany.
7
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
8
ReMediES, Department of General, Visceral and Transplantation Surgery, Hannover Medical School, and German Centre for Infection Research, Hannover-Braunschweig, Germany.
9
Institute for Cell and Gene Therapy, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, Hannover, Germany.
10
Institute for Virology, Medical Center University of Freiburg, Freiburg, Germany.
11
Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Abstract

During Coxsackievirus B3 (CVB3) infection hepatitis is a potentially life threatening complication, particularly in newborns. Studies with type I interferon (IFN-I) receptor (IFNAR)-deficient mice revealed a key role of the IFN-I axis in the protection against CVB3 infection, whereas the source of IFN-I and cell types that have to be IFNAR triggered in order to promote survival are still unknown. We found that CVB3 infected IFN-β reporter mice showed effective reporter induction, especially in hepatocytes and only to a minor extent in liver-resident macrophages. Accordingly, upon in vitro CVB3 infection of primary hepatocytes from murine or human origin abundant IFN-β responses were induced. To identify sites of IFNAR-triggering we performed experiments with Mx reporter mice, which upon CVB3 infection showed massive luciferase induction in the liver. Immunohistological studies revealed that during CVB3 infection MX1 expression of hepatocytes was induced primarily by IFNAR-, and not by IFN-III receptor (IFNLR)-triggering. CVB3 infection studies with primary human hepatocytes, in which either the IFN-I or the IFN-III axis was inhibited, also indicated that primarily IFNAR-, and to a lesser extent IFNLR-triggering was needed for ISG induction. Interestingly, CVB3 infected mice with a hepatocyte-specific IFNAR ablation showed severe liver cell necrosis and ubiquitous viral dissemination that resulted in lethal disease, as similarly detected in classical IFNAR-/- mice. In conclusion, we found that during CVB3 infection hepatocytes are major IFN-I producers and that the liver is also the organ that shows strong IFNAR-triggering. Importantly, hepatocytes need to be IFNAR-triggered in order to prevent virus dissemination and to assure survival. These data are compatible with the hypothesis that during CVB3 infection hepatocytes serve as important IFN-I producers and sensors not only in the murine, but also in the human system.

PMID:
30075026
PMCID:
PMC6107283
DOI:
10.1371/journal.ppat.1007235
[Indexed for MEDLINE]
Free PMC Article

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