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.
Highlights
Hepatitis B virus (HBV) is a noncytopathic, hepatotropic double-stranded DNA virus that causes acute and chronic hepatitis and increases the risk of hepatic cirrhosis and hepatocellular carcinoma (HCC)
MITA-related protein (MRP) was identified as a dominant negative mutant of MITA/STING, it retains the ability to activate NF-κB in 293T cells [29]
Consistent with reporter results, the phosphorylation of IRF3 but not IκB was induced by MITA/STING in a dose-dependent way, while the phosphorylation of IκB but not IRF3 was increased by MRP (Fig 1G and 1H)
Summary
Hepatitis B virus (HBV) is a noncytopathic, hepatotropic double-stranded DNA virus that causes acute and chronic hepatitis and increases the risk of hepatic cirrhosis and hepatocellular carcinoma (HCC). It is generally accepted that the vigor and quality of the cellular immune response determined whether HBV infection is cleared or persists. The adaptive immune responses to viral antigens, especially the destruction of infected cells and the non-lytic mechanisms eliminating. In addition to the adaptive immune response, the innate immune response induced by the recognition of pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) plays an indispensable role in controlling viral infection [4]. Once the PRR senses PAMPs, a series of signaling cascades are triggered, resulting in the activation of transcription factors IRF3 and NF-κB, the following production of interferon (IFN) and inflammatory cytokines, which restrict microbial invasion and further evocate the adaptive immune responses [16]
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