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J Hepatol. 2015 Aug;63(2):346-53. doi: 10.1016/j.jhep.2015.03.011. Epub 2015 Mar 17.

Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection.

Author information

1
I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Department for General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Germany.
3
I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, Germany.
4
IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany.
5
I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, Germany. Electronic address: m.dandri@uke.de.
6
I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Abstract

BACKGROUND & AIMS:

The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice.

METHODS:

Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.

RESULTS:

Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-ß, hIFN-ß and hIFN-λ) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling.

CONCLUSIONS:

Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes.

KEYWORDS:

Chronic viral hepatitis; HBV; HDV; ISG; uPA mice

PMID:
25795587
DOI:
10.1016/j.jhep.2015.03.011
[Indexed for MEDLINE]

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