Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood–borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood–brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS.

中文翻译：

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无乳链球菌破坏脑内皮细胞中的 P-糖蛋白功能

细菌性脑膜炎是一种严重的危及生命的中枢神经系统感染。为了引起脑膜炎，血源性细菌需要与构成血脑屏障的脑内皮细胞 (BEC) 相互作用并渗透。BEC 有助于维持大脑稳态，它们拥有一系列外排转运蛋白，如 P-糖蛋白 (P-gp)，其功能是将潜在有害化合物从 CNS 排回循环系统。通常，外排也用于限制治疗药物的大脑摄取，这是中枢神经系统药物递送的主要障碍。在脑膜炎期间，BEC 屏障完整性受到损害；然而，人们对感染期间外排运输的扰动知之甚少。因此，了解细菌感染对 P-gp 功能的影响对于治疗干预的潜在途径很重要。为此，脑膜细菌病原体无乳链球菌被发现抑制人诱导多能干细胞衍生的 BEC 中的 P-gp 活性，并且观察到的抑制需要活细菌。该观察结果与使用细菌性脑膜炎小鼠模型在体外和体内感染期间降低的 P-gp 表达相关。鉴于细菌相互作用对 P-gp 功能的影响，将这些发现纳入中枢神经系统细菌感染的药物递送范式分析将非常重要。该观察结果与使用细菌性脑膜炎小鼠模型在体外和体内感染期间降低的 P-gp 表达相关。鉴于细菌相互作用对 P-gp 功能的影响，将这些发现纳入中枢神经系统细菌感染的药物递送范式分析将非常重要。该观察结果与使用细菌性脑膜炎小鼠模型在体外和体内感染期间降低的 P-gp 表达相关。鉴于细菌相互作用对 P-gp 功能的影响，将这些发现纳入中枢神经系统细菌感染的药物递送范式分析将非常重要。