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Development of a Hepatitis B Virus Reporter System to Monitor the Early Stages of the Replication Cycle
Published on: February 1, 2017
MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication
Shuhui Liu1,2, Kaitao Zhao1,2, Xi Su1,2
1State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Abstract:
An efficient clearance of hepatitis B virus (HBV) requires the coordinated work of both the innate and adaptive immune responses. MITA/STING, an adapter protein of the innate immune signaling pathways, plays a key role in regulating innate and adaptive immune responses to DNA virus infection. Previously, we identified an alternatively spliced isoform of MITA/STING, called MITA-related protein (MRP), and found that MRP could specifically block MITA-mediated interferon (IFN) induction while retaining the ability to activate NF-κB. Here, we asked whether MITA/STING and MRP were able to control the HBV replication. Both MITA/STING and MRP significantly inhibited HBV replication in vitro. MITA overexpression stimulated IRF3-IFN pathway; while MRP overexpression activated NF-κB pathway, suggesting these two isoforms may inhibit HBV replication through different ways. Using a hydrodynamic injection (HI) mouse model, we found that HBV replication was reduced following MITA/STING and MRP expression vectors in mice and was enhanced by the knockout of MITA/STING (MITA/STING-/-). The HBV specific humoral and CD8+ T cell responses were impaired in MITA/STING deficient mice, suggesting the participation of MITA/STING in the initiation of host adaptive immune responses. In summary, our data suggest that MITA/STING and MRP contribute to HBV control via modulation of the innate and adaptive responses.
Insights
MITA/STING and its isoform MRP protein inhibit hepatitis B virus (HBV) replication by modulating innate and adaptive immunity. MITA/STING is crucial for initiating adaptive immune responses against HBV.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Hepatitis B virus (HBV) clearance depends on integrated innate and adaptive immune responses.
- MITA/STING is a key adapter protein in innate immunity, regulating responses to DNA viruses.
- An alternatively spliced isoform, MITA-related protein (MRP), selectively inhibits MITA-mediated interferon induction while activating NF-κB.
Purpose of the Study:
- To investigate the roles of MITA/STING and MRP in controlling HBV replication.
- To elucidate the distinct mechanisms by which MITA/STING and MRP influence HBV infection.
- To assess the impact of MITA/STING on adaptive immune responses during HBV infection.
Main Methods:
- In vitro assays to assess HBV replication inhibition by MITA/STING and MRP.
- Overexpression studies to analyze the activation of IRF3-IFN and NF-κB pathways.
- Hydrodynamic injection mouse model to evaluate the in vivo effects of MITA/STING and MRP.
- Analysis of HBV-specific humoral and CD8+ T cell responses in MITA/STING-deficient mice.
Main Results:
- Both MITA/STING and MRP significantly inhibited HBV replication in vitro.
- MITA/STING activated the IRF3-IFN pathway, while MRP activated the NF-κB pathway.
- Expression of MITA/STING and MRP vectors reduced HBV replication in mice.
- HBV replication was enhanced in MITA/STING-knockout mice.
- Mice deficient in MITA/STING exhibited impaired HBV-specific humoral and CD8+ T cell responses.
Conclusions:
- MITA/STING and MRP are critical regulators of innate and adaptive immunity against HBV.
- These proteins inhibit HBV replication through distinct signaling pathways.
- MITA/STING plays a vital role in initiating adaptive immune responses essential for controlling HBV infection.
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