Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication

Abstract

Hepatitis B virus (HBV) infection causes acute and chronic liver diseases, including severe hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Interferon alpha 2a (IFNα-2a) is commonly used for treating chronic HBV infection. However, its efficacy remains relatively low. Yet, the immunological and molecular mechanisms for successful IFNα-2a treatment remain elusive. One issue is whether the application of increasing IFNα doses may modulate cellular processes and HBV replication in hepatic cells. In the present study, we focused on the interaction of IFNα signaling with other cellular signaling pathways and the consequence for HBV replication. The results showed that with the concentration of 6000 U/ml IFNα-2a treatment downregulated the activity of not only the Akt/mTOR signaling but also the AMPK signaling. Additionally, IFNα-2a treatment increased the formation of the autophagosomes by blocking autophagic degradation. Furthermore, IFNα-2a treatment inhibited the Akt/mTOR signaling and initiated autophagy under low and high glucose concentrations. In reverse, inhibition of autophagy using 3-methyladenine (3-MA) and glucose concentrations influenced the expression of IFNα-2a-induced ISG15 and IFITM1. Despite of ISGs induction, HBV replication and gene expression in HepG2.2.15 cells, a cell model with continuous HBV replication, were slightly increased at high doses of IFNα-2a. In conclusion, our study indicates that IFNα-2a treatment may interfere with multiple intracellular signaling pathways, facilitate autophagy initiation, and block autophagic degradation, thereby resulting in slightly enhanced HBV replication.

The downregulation of Tapasin in dendritic cell regulates CD8+ T cell autophagy to hamper hepatitis B viral clearance in the induced pluripotent stem cell‐derived hepatocyte organoid

“…Our findings suggested that Tapasin‐shRNA transfection into DCs might activate mTOR and inhibit autophagy in CD8 + T cells to consequently weaken specific HBV immune responses. It is notable that IFN‐α2a treatment's downregulation of AKT/mTOR signaling augments autophagosome production by restraining autophagic degradation 22 …”

Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release

“…In reverse, some viruses require autophagic components for their own survival and replication, as their replication can be abolished by autophagy inhibitors ( Choi et al., 2018 ). In our published work, we demonstrated that IFN-α triggered autophagy and promoted HBV replication in an in-vitro study ( Li J. et al., 2022 ). Some viruses strategically exploit the early stages of autophagy and antagonize autophagosome maturation to prevent degradation ( Kyei et al., 2009 ; Lin et al., 2020a ), utilize autophagy-related lipid metabolism for efficient replication ( Heaton and Randall, 2010 ; Kim et al., 2017 ), while some even exploit autophagy as an assembly platform and release pathway ( Chu et al., 2022 ).…”

Types of Cell Death and Their Relations to Host Immunological Pathways

“…Research found a correlation between type 1 interferons and autophagy [24,29]. Type 1 interferon is an inducer of autophagy [30][31][32]. Interferon regulatory factor 1 (IRF1), which can activate interferon beta, is also related in autophagy [33].…”