Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei

Melioidosis is caused by the facultative intracellular bacterium burkholderia pseudomallei and is potentially fatal. despite a growing global burden and high fatality rate,little is known about the disease. recent studies demonstrate that cyclooxygenase-2 (cox-2) inhibition is an effective post-exposure therapeutic for pulmonary melioidosis,which works by inhibiting the production of prostaglandin e2 (pge2). this treatment,while effective,was conducted using an experimental cox-2 inhibitor that is not approved for human or animal use. therefore,an alternative cox-2 inhibitor needs to be identified for further studies. tolfenamic acid (ta) is a non-steroidal anti-inflammatory drug (nsaid) cox-2 inhibitor marketed outside of the united states for the treatment of migraines. while this drug was developed for cox-2 inhibition,it has been found to modulate other aspects of inflammation as well. in this study,we used raw 264.7 cells infected with b pseudomallei to analyze the effect of ta on cell survival,pge2 production and regulation of cox-2 and nuclear factor- kappab (nf-ĸb) protein expression. to evaluate the effectiveness of post-exposure treatment with ta,results were compared to ceftazidime (cz) treatments alone and the co-treatment of ta with a sub-therapeutic treatment of cz determined in a study of balb/c mice. results revealed an increase in cell viability in vitro with ta and were able to reduce both cox-2 expression and pge2 production while also decreasing nf-ĸb activation during infection. co-treatment of orally administered ta and a sub-therapeutic treatment of cz significantly increased survival outcome and cleared the bacterial load within organ tissue. additionally,we demonstrated that post-exposure ta treatment with sub-therapeutic cz is effective to treat melioidosis in balb/c mice. © 2016 wilson et al.