Leendertse Masja, Willems Rob J L, Giebelen Ida A J, van den Pangaart Petra S, Wiersinga W Joost, de Vos Alex F, Florquin Sandrine, Bonten Marc J M, van der Poll Tom
Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
J Immunol. 2008 Apr 1;180(7):4865-74. doi: 10.4049/jimmunol.180.7.4865.
The incidence of infections with Enterococcus faecium is increasing worldwide. TLRs have been implicated in the recognition of pathogens and the initiation of an adequate innate immune response. We here sought to determine the roles of MyD88, the common adaptor protein involved in TLR signaling, TLR2, TLR4, and CD14 in host defense against E. faecium peritonitis. MyD88 knockout (KO) mice demonstrated an impaired early response to E. faecium peritonitis, as reflected by higher bacterial loads in peritoneal fluid and liver accompanied by a markedly attenuated neutrophil influx into the abdominal cavity. In vitro, not only MyD88 KO macrophages but also TLR2 KO and CD14 KO macrophages displayed a reduced responsiveness to E. faecium. In accordance, transfection of TLR2 rendered human embryonic kidney 293 cells responsive to E. faecium, which was enhanced by cotransfection of CD14. TLR2 KO mice showed higher bacterial loads in peritoneal fluid after in vivo infection with E. faecium and a diminished influx of neutrophils, whereas CD14 KO mice had an unaltered host response. E. faecium phagocytosis and killing were not affected by MyD88, TLR2, or CD14 deficiency. TLR4 did not play a role in the immune response to E. faecium in vitro or in vivo. These data suggest that MyD88 contributes to the effective clearance of E. faecium during peritonitis at least in part via TLR2 and by facilitating neutrophil recruitment to the site of the infection.
在全球范围内,粪肠球菌感染的发生率正在上升。Toll样受体(TLRs)参与病原体识别及启动适当的固有免疫反应。我们在此旨在确定髓样分化因子88(MyD88,TLR信号传导中常见的衔接蛋白)、TLR2、TLR4和CD14在宿主抵御粪肠球菌性腹膜炎中的作用。MyD88基因敲除(KO)小鼠对粪肠球菌性腹膜炎的早期反应受损,这表现为腹腔液和肝脏中细菌载量更高,同时腹腔内中性粒细胞流入明显减少。在体外,不仅MyD88 KO巨噬细胞,而且TLR2 KO和CD14 KO巨噬细胞对粪肠球菌的反应性均降低。相应地,转染TLR2可使人胚肾293细胞对粪肠球菌产生反应,而共转染CD14可增强这种反应。TLR2 KO小鼠在体内感染粪肠球菌后,腹腔液中细菌载量更高,中性粒细胞流入减少,而CD14 KO小鼠的宿主反应未改变。MyD88、TLR2或CD14缺陷不影响粪肠球菌的吞噬和杀伤。TLR4在体外或体内对粪肠球菌的免疫反应中不起作用。这些数据表明,MyD88至少部分通过TLR2并通过促进中性粒细胞募集到感染部位,有助于在腹膜炎期间有效清除粪肠球菌。