Hepatitis B Virus (HBV) Upregulates TRAIL-R3 Expression in Hepatocytes Resulting in Escape From Both Cell Apoptosis and Suppression of HBV Replication by TRAIL.

Abstract

BACKGROUND:

Hepatitis B virus (HBV) evades host immunity by regulating intracellular signals. To clarify this immune tolerance mechanism, we performed gene expression analysis using HBV-infected humanized mouse livers.

METHODS:

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 3 (TRAIL-R3) was significantly upregulated in livers of HBV-infected human hepatocyte transplanted mice by cDNA microarray and next-generation sequencing. We analyzed the significance of TRAIL-R3 upregulation in HBV infection using human hepatocyte transplanted mice and HepG2 cell lines.

RESULTS:

TRAIL-R3 induction by HBV infection was verified by in vitro and in vivo HBV replication models, and induction was inhibited by antiviral nucleot(s)ide analogue treatment. TRAIL-R3 transcription was regulated by the TRAIL-R3 promoter at -969 to -479 nucleotides upstream from the transcription start site, and by hepatitis B x (HBx) via activation of nuclear factor-κB (NF-κB) signal. TRAIL not only induced cell apoptosis but also inhibited HBV replication. TRAIL-R3 upregulation could inhibit both TRAIL-dependent apoptosis in HBV-infected hepatocytes and TRAIL-mediated suppression of HBV replication.

CONCLUSIONS:

These results suggest a mechanism by which HBV persists by escaping host immunity through upregulation of TRAIL-R3. Development of novel drugs to inhibit this escape system might lead to complete HBV elimination from human hepatocytes.

• Authors: Yosuke Suehiro, Masataka Tsuge, Mio Kurihara, Takuro Uchida, Hatsue Fujino, Atsushi Ono, Masami Yamauchi, Grace Naswa Makokha, Takashi Nakahara, Eisuke Murakami, Hiromi Abe-Chayama, Tomokazu Kawaoka, Daiki Miki, Michio Imamura, Hiroshi Aikata, C Nelson Hayes, Takashi Fujita, Kazuaki Chayama
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 227 Issue 5 Pg. 686-695 (03 01 2023) ISSN: 1537-6613 [Electronic] United States
• PMID: 35226068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Trans-Activators
• Viral Regulatory and Accessory Proteins
• Ligands
• Tumor Necrosis Factor-alpha

Topics

• Humans
• Mice
• Animals
• Hepatitis B virus (physiology)
• Trans-Activators (metabolism)
• Viral Regulatory and Accessory Proteins (metabolism)
• Ligands
• Hepatocytes
• Apoptosis
• Hepatitis B
• Tumor Necrosis Factor-alpha (metabolism)
• Virus Replication