DC-specific HMGB1 KO mice clear vaccinia viral infection more effectively (VIR5P.1018)

Abstract

Abstract High-mobility group box 1 (HMGB1), an evolutionarily ancient and abundant DNA-binding protein within the nucleus, acts as a Damage Associated Molecular Pattern (DAMP) molecule extracellularly to promote immunity. It also functions in the cytosol to promote autophagy, a critical mechanism in viral clearance. HMGB1 is required for dendritic cell (DC) maturation and chemotaxis but how HMGB1 regulates DC function particularly in viral clearance is unclear. We constructed mice with HMGB1-knockout (KO) DCs (DCH) by crossing HMGB1 floxed mice with CD11c Cre mice. Although KO DCs differentiate normally from the bone marrow, they have diminished lymphocyte stimulatory capacity and polarize naive T cells towards Th17 and Treg phenotypes while wide type (WT) DCs induce IFNγ and IL-4 secretion at a ratio of 1:1 in allogeneic assays (p<.05). We infected DCH and WT mice with luc+ vaccinia and assayed viral infection over 9 days. Surprisingly, the virus is cleared more rapidly in the DCH cohort (p<.05). This is associated with increased T cells (p<.01) and CD11c+ cells (p<.05) within the spleen. We hypothesize that the proliferation of vaccinia depends on intact autophagy which may be impaired in KO DCs. We also find DCs release HMGB1 through exosomes, which are membrane vesicles enriched in MHC molecules and responsible for virus transmission. These results suggest that HMGB1 is not only critical for function but also contributes to the persistance of vaccinia virus in this murine model.