Francisella tularensis can cause a variety of different diseases dependent on the route of infection. Inhalational exposure causes a severe, acute respiratory infection. The immune response within the lung in inhalational mouse models of infection is temporal; demonstrating an initial lack of pro-inflammatory cytokine response, followed by an exponential increase (termed Cytokine Storm) 1-2 days prior to death. Both of these aspects contribute to the pathogenesis of the disease and therefore represent potential targets for the generation of post-exposure therapeutics. Over the last few years our laboratory has focused on understanding the overactive immune response and explored the use of anti-inflammatory compounds (either alone or in combination with antimicrobials) to potentially increase survival and/or extend time to death. We have demonstrated proof of principle that the use of a host-targeted therapy (i.e. anti-HMGB1 antibodies), in combination with levofloxacin during a F. tularensis Schu S4 infection can increase survival and widen the window of opportunity for traditional antibiotic treatments.
Recently we have explored the role of specific cell populations and regulators, important in maintaining immune homeostasis, during F. tularensis infection. We have demonstrated using KO mouse models that manipulation of the Regulatory T cell network and the CD200R pathway can alter the pathogenesis of disease by changing the overall cytokine profile.
Identification of key immune cells/ molecules such as these are essential in generating novel therapeutics to not only treat intracellular pathogens, but also reduce the emergence of antimicrobial resistance.
Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved