Antibiotic efficacy is greatly enhanced the earlier it is administered following infection with a bacterial pathogen. However, in a clinical setting antibiotic treatment usually commences following the onset of symptoms, which in some cases (e.g. Biothreat Agents) may be too late.In a BALB/c murine intra-nasal model of infection for Francisella tularensis SCHU S4 (F. tularensis) infection, we demonstrate during a time course that pro-inflammatory cytokines and the damage associated molecular pattern, HMGB1, were not significantly elevated above naive levels in tissue or sera until 72h post-infection. HMGB1 was identified as a potential therapeutic target that could extend the window of opportunity for the treatment of tularaemia with antibiotics.Antibodies to HMGB1 were administered in conjunction with a delayed/sub-optimal levofloxacin treatment of F. tularensis. We found in the intranasal model of infection that treatment with anti-HMGB1 antibody, when compared to an isotype IgY control antibody, conferred a significant survival benefit and decreased bacterial loads in the spleen and liver but not the lung (primary loci of infection) four days into infection. We also observed an increase in the production of interferon-γ in all tested organs.This data demonstrates that treatment with anti-HMGB1 antibody is beneficial in enhancing the effectiveness of current antibiotics in treating tularemia. Strategies, of this type, involving antibiotics in combination with immuno-modulatory drugs are likely to be essential for the development of a post-exposure therapeutic for intracellular pathogens.
