Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication.

Jia Li,Mengji Lu,Ruth Broering,Xueyu Wang,Zhenghong Yuan,Thekla Kemper,Jieliang Chen

doi:10.3389/fcimb.2022.804011

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.

Highlights

Hepatitis B virus (HBV) infection causes acute and chronic infections that results in the death of over 887,000 people every year due to severe hepatitis, liver cirrhosis, and cancer despite of effective vaccination (Polaris Observatory, 2018)
The levels of total and phosphorylated AMPK were decreased (Figure 1B). These data indicate that Interferon alpha 2a (IFNa-2a) attenuates Akt/mammalian target of rapamycin (mTOR) signaling and AMPK signaling
The secreted and intracellular HBsAg decreased after co-treatment with 3-MA (Figure 6E). All these results indicate that interferon alpha (IFNa)-2a enhances HBV replication at a high dose and this enhancement is dependent on autophagy

Summary

Introduction

Hepatitis B virus (HBV) infection causes acute and chronic infections that results in the death of over 887,000 people every year due to severe hepatitis, liver cirrhosis, and cancer despite of effective vaccination (Polaris Observatory, 2018). IFNa-2a is a cytokine with immunomodulatory and antiviral effects and is one of the first-line drugs for clinical treatment of chronic hepatitis B (CHB) (Cho and Kelsall, 2014). A great number of cellular genes are up-or downregulated by IFNa and many of those so-called IFNstimulated genes (ISGs) have antiviral functions (Schoggins and Rice, 2011; Schneider et al, 2014). IFNa subtypes differ in their antiviral and immunomodulatory functions (Chen et al, 2021). Besides the JAK/STAT, which are called canonical signaling pathways (Mazewski et al, 2020), IFNa is able to modulate multiple intracellular signaling pathways through non-canonical, including MAP kinase and phosphoinositide 3kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways (Mazewski et al, 2020). IFNa activates PI3K/Akt/ mTOR signaling pathway (Uddin et al, 1995; Lekmine et al, 2004) and initiates cellular autophagy

Methods

Results

Conclusion