Hepatitis B virus genomic nucleic acid in the activation and maturation of bone marrow-derived dendritic cells

Abstract

Hepatitis B virus (HBV) is the etiological agent that causes a self-limiting or chronic infection in the hepatocytes of about 250 million people worldwide. The role of adaptive immune system during HBV infection has been well studied. However, the innate immune system's responses against HBV during the early stage of infection largely remain unclear. In this study, we found that HBV genomic DNA or Salmon Sperm DNA (SSD) was able to induce the innate immune response in the macrophages cell line RAW264.7 but not the hepatocyte cell line, HepG2, indicating that hepatocytes may lack of a functional DNA-sensing pathway and hence are unable to respond to the presence of foreign DNA in the cytosol with type 1 IFN response. Thus, we hypothesized that non-parenchymal cells like the Antigen Presenting Cells (APC) might be crucial in triggering the initial immune response to suppress the virus replication and link the innate and adaptive responses. Using bone marrow-derived DCs (BMDC) as a model, this study demonstrated that HBV genomic DNA is able to induce cytokines like TNF-alpha, IL-6, and IL-12p40 secretion. We also examined the activation and maturation of BMDCs when exposed to the HBV genomic DNA intracellularly and extracellularly. A significant shift of CD86+ and CD40+ cell populations was observed during extracellular exposure of BMDC to Poly I:C and HBV genomic DNA, indicating that TLRs may be vital in the uptake of the extracellular viral DNA to activate the BMDCs. Moreover, transfection of intracellular nucleic acid stimuli, including HBV genomic DNA as well induced BMDCs maturation. Our findings highlight the critical function of DCs in antiviral response as a potential connection between the innate and adaptive immune systems during HBV pathogenesis. Nevertheless, further study is required to determine the role of cytosol DNA sensing pathway in DCs during HBV infection.