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Open AccessArticle

Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes

1
Host–Pathogen Interactions, Paul-Ehrlich-Institut, 63225 Langen, Germany
2
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
3
Regenerative Medicine and Experimental Surgery (ReMediES), Department of General, Visceral and Transplant Surgery, Hannover Medical School, 30625 Hannover, Germany
4
German Centre for Infection Research (DZIF), Hannover-Braunschweig, 38124 Braunschweig, Germany
5
Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, 35392 Giessen, Germany
6
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
7
German Center for Infection Research (DZIF), 69120 Heidelberg, Germany
8
German Center for Infection Research (DZIF), 63225 Langen, Germany
9
Sanford Burnham Prebys Medical Discovery Institute, Immunity and Pathogenesis Program, La Jolla, CA 92037, USA
*
Authors to whom correspondence should be addressed.
Current Address: Institute of Virology, Saarland University Medical Center, 66421 Homburg/Saar, Germany.
Viruses 2020, 12(6), 592; https://doi.org/10.3390/v12060592
Received: 27 April 2020 / Revised: 24 May 2020 / Accepted: 28 May 2020 / Published: 29 May 2020
(This article belongs to the Special Issue Innate Immune Sensing of Viruses and Viral Evasion)
Hepatitis B virus (HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway. View Full-Text
Keywords: hepatitis B virus (HBV); innate immunity; STING; cGAS; innate immune sensing; interferon response hepatitis B virus (HBV); innate immunity; STING; cGAS; innate immune sensing; interferon response
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MDPI and ACS Style

Lauterbach-Rivière, L.; Bergez, M.; Mönch, S.; Qu, B.; Riess, M.; Vondran, F.W.R.; Liese, J.; Hornung, V.; Urban, S.; König, R. Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes. Viruses 2020, 12, 592.

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