Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview

Abstract

Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.

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

“…TLR3 also recruits TRAF6 to phosphorylate TAK1. TAK1 sensitizes AP-1 via the activation of the MAPK pathway and activate NF-kB via the IKK-IkB complex to modulate the inflammatory reaction (33)(34)(35)(36)(37)(38).…”

“…Accumulating data shows that initiating the host TLR response is a new therapeutic strategy for HBV infection ( 36 , 37 ). Several studies have demonstrated that the stimulation of TLR2-5, TLR7, and TLR9 with their specific ligands can inhibit HBV replication in the cell and animal models ( 38 ). Furthermore, the potential of TLR agonists, including GS-9620, RO7020531, JNJ-64794964 (TLR7 agonists), GS-9688 (TLR8 agonist), and AIC649 (TLR9 agonist), has been investigated in clinical trials at different stages ( 38 , 39 ).…”

“…Several studies have demonstrated that the stimulation of TLR2-5, TLR7, and TLR9 with their specific ligands can inhibit HBV replication in the cell and animal models ( 38 ). Furthermore, the potential of TLR agonists, including GS-9620, RO7020531, JNJ-64794964 (TLR7 agonists), GS-9688 (TLR8 agonist), and AIC649 (TLR9 agonist), has been investigated in clinical trials at different stages ( 38 , 39 ). HBV is considered as a “stealth virus,” and the suppression of TLR signaling molecules has been reported in different kinds of cells in patients with HBV infection ( 40 , 41 ).…”

“…Furthermore, several studies have shown that multiple virus-encoded proteins, including HBsAg, HBeAg, and HBV polymerase, contribute to HBV persistence by inhibiting TLR-mediated antiviral responses ( 38 ). For instance, HBsAg can inhibit TLR3-mediated immune response in murine Kupffer cells and sinusoidal endothelial cells ( 50 ).…”

An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

“…There is a growing interest in the use of TLR agonists as immunomodulators for the treatment of inflammation, cancer, infection, allergy, and autoimmunity. The use of TLR agonists to modify immunotherapeutic effects also appears promising [93][94][95][96][97][98][99]. Moreover, TLRs, which are considered as important triggering molecules of trained immunity, trigger a long-term boosting of innate immune responses [100].…”