Manganese Breaks the Immune Tolerance of HBs-Ag.

BACKGROUND

Manganese (Mn has been shown to promote type I interferon (IFN) production and activate the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) signaling pathway, suggesting that Mn could be used as an adjuvant for vaccination.

METHODS

In present study, the effects of Mn on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn with or without adeno-associated virus (AAV)-HBV infection. Expression of IFN-α and IFN-β and activation of TBK1 and IRF3 were monitored. Wild-type and STING mice were treated with Mn and then infected with AAV-HBV. Serum levels of HBV surface antigen (HBsAg), alanine aminotransferase (ALT) activity, IFN-α, and IFN-β were detected. Lymphocyte infiltration in the liver was evaluated. HBsAg-Tg mice were vaccinated with Mn and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-β were monitored after vaccination.

RESULTS

Mn promoted IFN-α and IFN-β production in mouse hepatocytes and kuppfer cells. Mn failed to promote IFN-α and IFN-β production in kuppfer cells deficient in STING. Mn promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn decreased serum levels of HBsAG, increased serum levels of alanine aminotransferase (ALT), IFN-α and IFN-β, and enhanced lymphocyte infiltration and the percentage of IFN-γ-producing CD8 T cells in the liver of AAV-HBV-infected mice. In contrast, Mn treatment did not affect serum levels of HBsAG, ALT, IFN-α, or IFN-β in STING-deficient mice.

CONCLUSIONS

Mn promoted HBsAG antibody, ALT, and IFN-β production after HBsAG immunization. Mn promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.