HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients.

Bingqing Zheng,Huajun Zhao,Zhaoyi Pan,Yujie Feng,Yating Yu,Qiuju Han,Jian Zhang

doi:10.3390/ijms22147643

Bingqing Zheng, Huajun Zhao + Show 5 more

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https://doi.org/10.3390/ijms22147643

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Abstract

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.

Highlights

We found that Stimulator of IFN genes (STING) was significantly lower in Natural killer (NK) cells from hepatitis B envelope antigen (HBeAg)-negative chronic hepatitis B virus (CHB) patients than in NK cells from healthy donors (Figure 1A), but no significant differences between CD3- CD56bright and
The results showed that the level of IFN-α was increased in NK cells from healthy donors by 20 30 -cGAMP treatment, accompanied with the activation of IFN regulatory factor 3 (IRF3) (Figure 6A,B)
Studies have demonstrated that STING deficiency in hepatocytes significantly impairs the anti-virus response, which partly explains hepatocyte immune tolerance to Hepatitis B virus (HBV) infection [31,38]

Summary

Introduction

Hepatitis B virus (HBV) is DNA pathogenic virus that can cause chronic hepatitis, which is one of the major risk factors of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The innate immune system is the first line for defense against virus invasion, which recognizes pathogen-associated molecular patterns (PAMP) by a series of pattern recognition receptors (PRRs) [6,7,8,9]. Studies have indicated that DNA and RNA recognition signals of the innate immune system were injured during chronic HBV infection, especially the downregulation of toll-like receptors (TLRs) and the dysfunction of the type I IFN response, inducing persistent HBV [10,11,12,13]. HBsAg and HBeAg could inhibit TLR2 and TLR4 signaling-associated immune response of dendritic cells and monocytes [15,16,17]

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