Post-Exposure Therapeutic Efficacy of COX-2 Inhibition against <i>Burkholderia pseudomallei</i>

<div><p><i>Burkholderia pseudomallei</i> is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of <i>B. pseudomallei</i> impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE₂) production plays a regulatory role in the pathogenesis of <i>B. pseudomallei</i>. PGE₂ promotes <i>B. pseudomallei</i> intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE₂-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of <i>B. pseudomallei</i> in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to <i>B. pseudomallei</i>-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with <i>B. pseudomallei</i> and other intracellular pathogens.</p>