Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection

Abstract

As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

Innate Immunity, Inflammation, and Intervention in HBV Infection

“…JAK/STAT consists of three components: the tyrosine kinase receptor receiving the signal, the tyrosine kinase transmitting the signal-JAK, and the transcription factor producing the effect-STAT [ 43 , 44 ]. As the downstream pathway of IFN receptors, the JAK/STAT signaling must respond rapidly to initiate ISG production [ 45 ]. HBx-mediated JAK/STAT activation plays an important role in stimulating innate immune response during HBV infection.…”

What role for cellular metabolism in the control of hepatitis viruses?

“…Intricate interactions between hepatitis viruses and TLRs have been reported with both activating and inhibiting effects ( 27 , 28 ). At steady state, in primary human hepatocytes (PHH), only the expression of TLR3, 4 and 5 could be detected at the protein level.…”

“…HCV components can also be sensed by TLRs such as HCV Core that is recognized by human TLR2 ( 34 ). Conversely, hepatitis viruses have evolved countermeasures to block TLR signaling ( 28 ). For example, the NS3/4A protease of HCV is able to cleave TRIF, the signaling adaptor recruited by TLR3 ( 35 ).…”

The emerging role of DEAD/H-box helicases in hepatitis B virus infection

“…Additionally, DDX5 enhances the activation of interferon (IFN) signaling to suppress HBV replication. Activation of the JAK/STAT pathway plays a vital role in the antiviral response induced by IFN (Kong et al, 2021b;You et al, 2022). Sun et al showed that DDX5 could bind to STAT1 mRNA and modulate its translation by resolving a secondary RNA structure, namely the G-quadruplex, which is in the STAT1 mRNA 5'untranslated region (UTR) to accelerate its expression and activation to facilitate the sensitization of IFN-a signaling (Sun et al, 2022) (Figure 2).…”

“…Because of the lack of CARDs, LGP2 is considered incompetent and inhibits RIG-I-or MDA5mediated signaling. After MAVS is activated, it further induces the sensitization of TBK1, which initiates IKK-dependent phosphorylation of NF-kB and leads to IRF3 activation to facilitate the production of inflammatory factors and IFN (You et al, 2022). Current evidence indicates that RIG-I is a viral RNA sensor with the ability to recognize the 5'-ϵ region of HBV pgRNA and induce IFN expression to inhibit infection (Figure 2) (Sato et al, 2015).…”