Post-Exposure Therapeutic Efficacy of COX-2 Inhibition against Burkholderia pseudomallei

Burkholderia pseudomallei 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 B. pseudomallei 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 B. pseudomallei. PGE2 promotes B. pseudomallei 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 B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens.

类鼻疽伯克霍尔德菌（Burkholderia pseudomallei）是一种革兰氏阴性兼性胞内杆菌，亦是类鼻疽病的致病病原体——该疾病在东南亚与澳大利亚北部流行，病情危重。与其他多重耐药病原体类似，类鼻疽伯克霍尔德菌所具备的固有抗生素耐药性会阻碍临床治疗，这也凸显出开发能够规避抗菌耐药机制的替代治疗策略的迫切需求。本研究证实，宿主前列腺素E2（PGE2）的生成在类鼻疽伯克霍尔德菌的致病机制中发挥调控作用。在肺类鼻疽小鼠模型中，PGE2可促进类鼻疽伯克霍尔德菌在巨噬细胞内的胞内存活，并增强该菌的毒力。PGE2介导的巨噬细胞杀菌效应功能免疫抑制，与精氨酸酶2（Arg2）表达上调及一氧化氮（NO）生成减少显著相关。使用市售COX-2抑制剂进行干预，可抑制巨噬细胞内类鼻疽伯克霍尔德菌的增殖；当对类鼻疽伯克霍尔德菌感染小鼠于感染暴露后给药时，该抑制剂可为其提供针对快速致死性肺类鼻疽的显著保护作用。COX-2抑制疗法或可成为控制类鼻疽伯克霍尔德菌及其他胞内病原体感染的新型免疫治疗策略。