Abstract
Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.
Highlights
Hepatitis B virus (HBV) infection causes acute and chronic necroinflammatory hepatitis
To identify the immune effectors of innate immunity that eliminate HBV from the liver, we monitored the persistence of HBsAg in a panel of gene knockout mice, including Nod-like receptor family protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), myeloid differentiation primary response gene 88 (MYD88), IL-1 receptor (IL-1R), IFNa/b receptor (IFNAR), and tumor necrosis factor-a (TNF-a)
The results (Figure 1) demonstrate that HBV viral clearance is not significantly different from wild type C57BL/6 mice in IFN-a/b receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these effectors are not required for HBV clearance
Summary
Hepatitis B virus (HBV) infection causes acute and chronic necroinflammatory hepatitis. In an acute HBV infection, cessation of virus replication and clearance of viral transcripts and antigens from the liver depends on HBV-specific cytotoxic T cells [1,2]. A transient though slight activation of IFN-a genes was detected in human hepatocytes infected by HBV in chimeric mice [9], in support of the innate immunity to sense and react to HBV. A number of recent studies [10,11,12] has been investigated in suggesting the involvement of NK cells in chronic HBV infection and they could play a role in liver damage during reactivation. The role of innate immunity in viral clearance during HBV infection is still not clear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
