Manganese Breaks the Immune Tolerance of HBs-Ag

Background. Manganese (Mn2+) 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 Mn2+ could be used as an adjuvant for vaccination. Methods. In present study, the effects of Mn2+ on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn2+ with or without adeno-associated virus (AAV)-HBV infection. Expression of IFN-alpha and IFN-beta and activation of TBK1 and IRF3 were monitored. Wild-type and STING(-/-) mice were treated with Mn2+ and then infected with AAV-HBV. Serum levels of HBV surface antigen (HBsAg), alanine aminotransferase (ALT) activity, IFN-alpha, and IFN-beta were detected. Lymphocyte infiltration in the liver was evaluated. HBsAg-Tg mice were vaccinated with Mn2+ and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-beta were monitored after vaccination. Results. Mn2+ promoted IFN-alpha and IFN-beta production in mouse hepatocytes and kuppfer cells. Mn2+ failed to promote IFN-alpha and IFN-beta production in kuppfer cells deficient in STING. Mn2+ promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn2+ decreased serum levels of HBsAG, increased serum levels of alanine aminotransferase (ALT), IFN-alpha and IFN-beta, and enhanced lymphocyte infiltration and the percentage of IFN-gamma-producing CD8(+) T cells in the liver of AAV-HBV-infected mice. In contrast, Mn2+ treatment did not affect serum levels of HBsAG, ALT, IFN-alpha, or IFN-beta in STING-deficient mice. Conclusions. Mn2+ promoted HBsAG antibody, ALT, and IFN-beta production after HBsAG immunization. Mn2+ promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.

Automated summary

Manganese (Mn2+) has been shown to promote IFN-alpha and IFN-beta production and activate TBK1 and IRF3, potentially serving as an adjuvant for HBV vaccination. In HBV infection and vaccination, Mn2+ can enhance type I interferon production and immune cell function.