Loh Lip Nam, Gao Geli, Tuomanen Elaine I
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
mBio. 2017 Jan 3;8(1):e02030-16. doi: 10.1128/mBio.02030-16.
The Gram-positive bacterial cell wall (CW) peptidoglycan-teichoic acid complex is released into the host environment during bacterial metabolism or death. It is a highly inflammatory Toll-like receptor 2 (TLR2) ligand, and previous in vivo studies have demonstrated its ability to recapitulate pathological features of pneumonia and meningitis. We report that an actin-dependent pathway is involved in the internalization of the CW by epithelial and endothelial cells, in addition to the previously described platelet-activating factor receptor (PAFr)-dependent uptake pathway. Unlike the PAFr-dependent pathway, which is mediated by clathrin and dynamin and does not lead to signaling, the alternative pathway is sensitive to 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and engenders Rac1, Cdc42, and phosphatidylinositol 3-kinase (PI3K) signaling. Upon internalization by this macropinocytosis-like pathway, CW is trafficked to lysosomes. Intracellular CW trafficking is more complex than previously recognized and suggests multiple points of interaction with and without innate immune signaling.
Streptococcus pneumoniae is a major human pathogen infecting the respiratory tract and brain. It is an established model organism for understanding how infection injures the host. During infection or bacterial growth, bacteria shed their cell wall (CW) into the host environment and trigger inflammation. A previous study has shown that CW enters and crosses cell barriers by interacting with a receptor on the surfaces of host cells, termed platelet-activating factor receptor (PAFr). In the present study, by using cells that are depleted of PAFr, we identified a second pathway with features of macropinocytosis, which is a receptor-independent fluid uptake mechanism by cells. Each pathway contributes approximately the same amount of cell wall trafficking, but the PAFr pathway is silent, while the new pathway appears to contribute to the host inflammatory response to CW insult.
革兰氏阳性菌细胞壁（CW）的肽聚糖-磷壁酸复合物在细菌代谢或死亡过程中释放到宿主环境中。它是一种高度炎性的Toll样受体2（TLR2）配体，先前的体内研究已证明其能够重现肺炎和脑膜炎的病理特征。我们报告，除了先前描述的血小板活化因子受体（PAFr）依赖性摄取途径外，肌动蛋白依赖性途径也参与上皮细胞和内皮细胞对CW的内化。与由网格蛋白和发动蛋白介导且不导致信号传导的PAFr依赖性途径不同，另一种途径对5-（N-乙基-N-异丙基）阿米洛利（EIPA）敏感，并引发Rac1、Cdc42和磷脂酰肌醇3激酶（PI3K）信号传导。通过这种类似巨胞饮作用的途径内化后，CW被转运至溶酶体。细胞内CW的运输比先前认为的更为复杂，提示存在与固有免疫信号传导有关和无关的多个相互作用点。
肺炎链球菌是感染呼吸道和大脑主要的人类病原体。它是理解感染如何损伤宿主的成熟模式生物。在感染或细菌生长过程中，细菌将其细胞壁（CW）释放到宿主环境中并引发炎症。先前的一项研究表明，CW通过与宿主细胞表面的一种受体（称为血小板活化因子受体（PAFr））相互作用进入并穿过细胞屏障。在本研究中，通过使用缺乏PAFr的细胞，我们鉴定出了另一种具有巨胞饮作用特征的途径，巨胞饮作用是细胞的一种不依赖受体的液体摄取机制。每条途径对细胞壁运输的贡献大致相同，但PAFr途径不引发信号，而新途径似乎对宿主对CW损伤的炎症反应有贡献。
