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

Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei.
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Wilson WJ, Afzali MF, Cummings JE, Legare ME, Tjalkens RB, Allen CP, Slayden RA, Hanneman WH,


Wilson WJ, Afzali MF, Cummings JE, Legare ME, Tjalkens RB, Allen CP, Slayden RA, Hanneman WH, (click to view)

Wilson WJ, Afzali MF, Cummings JE, Legare ME, Tjalkens RB, Allen CP, Slayden RA, Hanneman WH,

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PLoS neglected tropical diseases 2016 Oct 2810(10) e0005065 doi 10.1371/journal.pntd.0005065
Abstract

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.

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