title: Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei.
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.
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
authors: William J
authors: http://orcid.org/0000-0002-8826-796X
authors: WJ
authors: Wilson
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Maryam F
authors: MF
authors: Afzali
authors: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Jason E
authors: JE
authors: Cummings
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Marie E
authors: ME
authors: Legare
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Ronald B
authors: RB
authors: Tjalkens
authors: Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Christopher P
authors: CP
authors: Allen
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Richard A
authors: RA
authors: Slayden
authors: Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
authors: William H
authors: WH
authors: Hanneman
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei / Q000276:immunology / Q000502:physiology*; D002442:Ceftazidime / Q000008:administration & dosage; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008554:Melioidosis / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D056990:Post-Exposure Prophylaxis; D062367:ortho-Aminobenzoates / Q000008:administration & dosage*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D002442:Ceftazidime; D051546:Cyclooxygenase 2