Anantharajah Ahalieyah, Faure Emmanuel, Buyck Julien M, Sundin Charlotta, Lindmark Tuulikki, Mecsas Joan, Yahr Timothy L, Tulkens Paul M, Mingeot-Leclercq Marie-Paule, Guery Benoît, Van Bambeke Françoise
Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
EA7366, Host-Pathogen Translational Research Group, Faculté de Médecine, Université Lille Nord de France, Lille, France.
J Infect Dis. 2016 Oct 1;214(7):1105-16. doi: 10.1093/infdis/jiw295. Epub 2016 Jul 13.
With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are 2 virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces interleukin 1β (IL-1β) release and reduces interleukin 17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination and IL-1β secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality, as evidenced by a reduction in secretory activity and flagellar motility and an increase in adenosine triphosphate levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising therapeutic approach.
随着多重耐药性的增加，铜绿假单胞菌感染需要替代治疗方法。注射体（iT3SS）和鞭毛（fT3SS）III型分泌系统是与不良临床结果相关的两种毒力因子。iT3SS将毒素、杆状蛋白、针状蛋白或调节蛋白以及鞭毛蛋白转运到宿主细胞质中，导致细胞毒性和NLRC4依赖性炎性小体激活，进而诱导白细胞介素1β（IL-1β）释放，并减少白细胞介素17（IL-17）的产生和细菌清除。fT3SS确保细菌的运动性、与宿主细胞的附着，并引发炎症。INP1855是通过体外筛选，利用假结核耶尔森菌鉴定出的一种iT3SS抑制剂。使用铜绿假单胞菌肺部感染的小鼠模型，我们发现INP1855可提高感染iT3SS阳性菌株后的生存率，降低细菌致病性、传播以及IL-1β分泌，并增加IL-17分泌。INP1855还改变了感染iT3SS阴性、fT3SS阳性菌株小鼠的细胞因子平衡。在体外，INP1855损害了iT3SS和fT3SS的功能，这可通过分泌活性和鞭毛运动性降低以及三磷酸腺苷水平升高得到证明。结果，INP1855降低了由毒素介导的细胞毒性以及实验室菌株和临床分离株诱导的炎性小体激活。我们得出结论，INP1855通过双重抑制iT3SS和fT3SS发挥作用，代表了一种有前景的治疗方法。
