Manganese Breaks the Immune Tolerance of HBs-Ag

BACKGROUND: Manganese (Mn(2+)) 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(2+) could be used as an adjuvant for vaccination. METHODS: In present study, the effects of Mn(2+) on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn(2+) 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(2+) 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(2+) and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-β were monitored after vaccination. RESULTS: Mn(2+) promoted IFN-α and IFN-β production in mouse hepatocytes and kuppfer cells. Mn(2+) failed to promote IFN-α and IFN-β production in kuppfer cells deficient in STING. Mn(2+) promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn(2+) 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(2+) treatment did not affect serum levels of HBsAG, ALT, IFN-α, or IFN-β in STING-deficient mice. CONCLUSIONS: Mn(2)(+) promoted HBsAG antibody, ALT, and IFN-β production after HBsAG immunization. Mn(2+) promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.