Role of p38 MAP kinase and transforming growth factor-β signaling in transepithelial migration of invasive bacterial pathogens
Role of p38 MAP kinase and transforming growth factor-β signaling in transepithelial migration of invasive bacterial pathogens
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DOI：
10.1074/jbc.m703576200
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发表时间：
2007-09-28
影响因子：
4.8
通讯作者：
Weiser, Jeffrey N.
中科院分区：
文献类型：
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作者：
Beisswenger, Christoph;Coyne, Carolyn B.;Weiser, Jeffrey N.
肺炎链球菌和流感嗜血杆菌是人类病原体，通常在上呼吸道粘膜表面无症状定植，但偶尔也会引起侵袭性疾病。这些物种穿越气道粘膜上皮的能力在体外用极化呼吸上皮细胞培养模型。在跨越上皮屏障的迁移之前，会失去经上皮抵抗。含脂磷胆酸的肺炎链球菌膜产物以toll样受体2依赖的方式诱导上皮屏障的破坏。这一结果与最近的一项遗传学研究相关联，该研究认为TLR2信号的增加与人类侵袭性肺炎球菌疾病的发病率增加有关。TLR2配体的上皮耐药丧失与p38 MAP激酶和转化生长因子(TGF)- β信号的激活有关。体内实验也证实了鼻腔感染肺炎链球菌后上皮细胞中p38 MAPK和tgf - β信号的激活。抑制p38 MAPK或tgf - β信号足以抑制肺炎链球菌或流感嗜血杆菌的迁移。我们的数据表明，不同的细菌利用共同的机制，包括MAPK和tgf - β信号通路来破坏上皮屏障并促进入侵。
Streptococcus pneumoniae and Haemophilus influenzae are human pathogens that often asymptomatically colonize the mucosal surface of the upper respiratory tract, but also occasionally cause invasive disease. The ability of these species to traverse the epithelium of the airway mucosa was modeled in vitro using polarized respiratory epithelial cells in culture. Migration across the epithelial barrier was preceded by loss of transepithelial resistance. Membrane products of S. pneumoniae that included lipoteichoic acid induced disruption of the epithelial barrier in a Toll-like receptor 2-dependent manner. This result correlates with a recent genetic study that associates increased TLR2 signaling with increased rates of invasive pneumococcal disease in humans. Loss of transepithelial resistance by the TLR2 ligand correlated with activation of p38 MAP kinase and transforming growth factor ( TGF)-beta signaling. Activation of p38 MAPK and TGF-beta signaling in epithelial cells upon nasal infection with S. pneumoniae was also demonstrated in vivo. Inhibition of either p38 MAPK or TGF-beta signaling was sufficient to inhibit the migration of S. pneumoniae or H. influenzae. Our data shows that diverse bacteria utilize common mechanisms, including MAPK and TGF-beta signaling pathways to disrupt epithelial barriers and promote invasion.