Natural killer cell activation contributes to hepatitis B viral control in a mouse model

Shiwen Tong,Hong Ren,Shiying Li,Minghong Li,Wenwei Yin,Hong Peng,Xiumei Li,Guangze Liu,Qian Liu

doi:10.1038/s41598-017-00387-2

Abstract

The roles of CD4 + T cells and CD8 + T cells in hepatitis B virus (HBV) infection have been well documented. However, the role of innate immunity in HBV infection remains obscure. Here we examined the effect of activation of innate immunity by polyinosinic: polycytidylic acid (PolyI:C) on HBV infection. A chronic HBV replication mouse model was established by hydrodynamical injection of pAAV/HBV1.2 plasmid into C57BL/6 mice. We found that HBV did not seem to induce an active NK-cell response in the mouse model. Early PolyI:C treatment markedly decreased serum HBV levels and led to HBV clearance. Following PolyI:C injection, NK cells were activated and accumulated in the liver. Depletion of NK cells markedly attenuated the anti-HBV activity of PolyI:C. Moreover, we found that IFN-γ production from NK cells was essential for the antiviral effect of PolyI:C in the model. Importantly, activation of NK cells by PolyI:C could also lead to HBV suppression in HBV-tolerant mice and HBV-transgenic mice. These results suggest that activated NK cells might suppress HBV and contribute to HBV clearance during natural HBV infection. In addition, therapeutic activation of NK cells may represent a new strategy for the treatment of chronic HBV infection.

Highlights

The hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that causes acute and chronic hepatitis often leading to liver cirrhosis as well as hepatocellular carcinoma[1]
We found that polycytidylic acid (PolyI):C treatment could control HBV infection in a Natural killer (NK) cell and IFN-γ-dependent manner
To address whether activation of innate immune system could influence the final outcomes of HBV infection, we utilized a nontransgenic HBV-carrier mouse model developed by hydrodynamic injection of the pAAV/HBV1.2 plasmid into C57BL/6 mice[19]

Summary

Introduction

The hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that causes acute and chronic hepatitis often leading to liver cirrhosis as well as hepatocellular carcinoma[1]. The outcome of HBV infection in humans (viral clearance or viral persistence) is determined by complicated, as yet not fully understood, interactions between HBV and the immune system[3] Both innate and adaptive components of the immune system mediate protective immunity against a viral infection, with innate responses being important for limiting viral replication and spreading very early after infection, as well as for a timely orchestration of virus-specific adaptive responses[4]. Natural killer (NK) cells have been viewed as the most important effectors of the initial antiviral innate immune system[11] Compared with their relatively low frequency in the peripheral lymphatic system, NK cells are highly enriched in the liver[12, 13], the site of HBV replication, implying that HBV has to evade NK cell-mediated immune responses to establish a persistent viral infection[14]. We found that PolyI:C treatment could control HBV infection in a NK cell and IFN-γ-dependent manner

Methods

Results

Conclusion