Hepatitis B Virus–Induced Imbalance of Inflammatory and Antiviral Signaling by Differential Phosphorylation of STAT1 in Human Monocytes

Abstract

It is not clear how hepatitis B virus (HBV) modulates host immunity during chronic infection. In addition to the key mediators of inflammatory response in viral infection, monocytes also express a high-level IFN-stimulated gene, CH25H, upon response to IFN-α exerting an antiviral effect. In this study, the mechanism by which HBV manipulates IFN signaling in human monocytes was investigated. We observed that monocytes from chronic hepatitis B patients express lower levels of IFN signaling/stimulated genes and higher levels of inflammatory cytokines compared with healthy donors. HBV induces monocyte production of inflammatory cytokines via TLR2/MyD88/NF-κB signaling and STAT1-Ser727 phosphorylation and inhibits IFN-α–induced stat1, stat2, and ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10–dependent, partially autocrine manner. Further, we found that enhancement of STAT1 activity with a small molecule (2-NP) rescued HBV-mediated inhibition of IFN signaling and counteracted the induction of inflammatory cytokines. In conclusion, HBV contributes to the monocyte inflammatory response but inhibits their IFN-α/β responsiveness to impair antiviral innate immunity. These effects are mediated via differential phosphorylation of Tyr701 and Ser727 of STAT1.

Hepatitis B Virus Particles Activate Toll‐Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes

“…Accordingly, HBV-induced production of inflammatory cytokines in monocytes depends on TLR2/MyD88/NFκB signaling. (25) Although the initial immune responses were transient in vitro, it is likely that this innate signaling in vivo is one of the first steps in a line of defense mechanisms leading to HBV clearance. Pathogen recognition receptors play a central role in innate immunity and have been recognized to affect chronic viral hepatitis.…”

“…(37) Interestingly, Song et al showed that whole HBV particles as well as HBsAg, purified from human plasma, activate TLR2 signaling in monocytes. (25) This leads to suggest that naturally occurring HBsAg, but not a recombinant one, harbors TLR2-activating potential. Here, HBV particles on the whole efficiently triggered TLR2mediated inflammatory responses in hepatocytes.…”

“…Song et al further showed that monocytes, derived from patients chronically infected with HBV, exhibit elevated expression of inflammatory cytokines. (25) The role of HBeAg has not been addressed in that publication, but it might be suggested that increased TLR2 expression in HBeAg-negative patients results in increased inflammatory responses. The present work leads to suggest that the receptor binding-related immune responses, induced by purified HBV particles, occurred independently of the presence of HBeAg.…”

“…Furthermore, Kupffer cells and monocytes are likely to show TLR2 induction after HBV exposure. (25,37) In the humanized mouse liver, where only hepatocytes are of human origin, we could not differentiate whether this induction was derived from murine hepatocytes or nonparenchymal liver cells. Thus, we propose that hepatic immune activation depends on both the intrinsic activation of the infected hepatocyte and the interplay of parenchymal and nonparenchymal liver cells.…”

Immune suppression in chronic hepatitis B infection associated liver disease: A review

“…Further experiments in vitro showed that HBsAg or HBV directly induced the expression of PD-L1 and HLA-E and the secretion of anti-inflammatory cytokines of monocytes from healthy adults[11]. Our group recently reported that HBV induces monocyte production of inflammatory cytokines via TLR2/MyD88/NF-κB signaling and STAT1-Ser727 phosphorylation and inhibits interferon (IFN)-α-induced stat1, stat2, and ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10-dependent, partially autocrine manner[12]. Therefore, HBV-induced suppressive monocytes/macrophages play a key role in the immune pathogenesis of chronic persistent infection.…”