Hepatitis B Virus (HBV) Upregulates TRAIL-R3 Expression in Hepatocytes Resulting in Escape From Both Cell Apoptosis and Suppression of HBV Replication by TRAIL. (28th February 2022)

• Record Type: Journal Article
• Authors: Suehiro, Yosuke; Tsuge, Masataka; Kurihara, Mio; Uchida, Takuro; Fujino, Hatsue; Ono, Atsushi; Yamauchi, Masami; Naswa Makokha, Grace; Nakahara, Takashi; Murakami, Eisuke; Abe-Chayama, Hiromi; Kawaoka, Tomokazu; Miki, Daiki; Imamura, Michio; Aikata, Hiroshi; Nelson Hayes, C; Fujita, Takashi; Chayama, Kazuaki
• Is Part Of: Journal of infectious diseases. Volume 227:Number 5(2023)
• Page Start: 686
• Page End: 695
• Publication Date: 2022-02-28
• Subjects: HBV -- TRAIL-R3 -- HBx -- apoptosis -- immune response; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiac044
• Languages: English
• ISSNs: 0022-1899

Abstract

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. Abstract : HBV infection caused TRAIL-R3 upregulation in both HBV-transfected HepG2 cell lines and HBV-infected mice livers. TRAIL-R3 upregulation inhibited both TRAIL-dependent apoptosis and suppression of HBV replication by TRAIL. HBV might persist by escaping host immunity through upregulation of TRAIL-R3.