Lee C A, Silva M, Siber A M, Kelly A J, Galyov E, McCormick B A
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12283-8. doi: 10.1073/pnas.97.22.12283.
In response to Salmonella typhimurium, the intestinal epithelium generates an intense inflammatory response consisting largely of polymorphonuclear leukocytes (neutrophils, PMN) migrating toward and ultimately across the epithelial monolayer into the intestinal lumen. It has been shown that bacterial-epithelial cell interactions elicit the production of inflammatory regulators that promote transepithelial PMN migration. Although S. typhimurium can enter intestinal epithelial cells, bacterial internalization is not required for the signaling mechanisms that induce PMN movement. Here, we sought to determine which S. typhimurium factors and intestinal epithelial signaling pathways elicit the production of PMN chemoattractants by enterocytes. Our results suggest that S. typhimurium activates a protein kinase C-dependent signal transduction pathway that orchestrates transepithelial PMN movement. We show that the type III effector protein, SipA, is not only necessary but is sufficient to induce this proinflammatory response in epithelial cells. Our results force us to reconsider the long-held view that Salmonella effector proteins must be directly delivered into host cells from bacterial cells.
针对鼠伤寒沙门氏菌，肠道上皮会产生强烈的炎症反应，主要由多形核白细胞（中性粒细胞，PMN）组成，这些细胞向并最终穿过上皮单层迁移到肠腔。研究表明，细菌与上皮细胞的相互作用会引发炎症调节因子的产生，促进PMN跨上皮迁移。尽管鼠伤寒沙门氏菌能够进入肠道上皮细胞，但诱导PMN移动的信号机制并不需要细菌内化。在此，我们试图确定哪些鼠伤寒沙门氏菌因子和肠道上皮信号通路会促使肠细胞产生PMN趋化因子。我们的结果表明，鼠伤寒沙门氏菌激活了一条蛋白激酶C依赖性信号转导通路，该通路协调PMN跨上皮移动。我们发现III型效应蛋白SipA不仅是诱导上皮细胞这种促炎反应所必需的，而且是充分的。我们的结果迫使我们重新审视长期以来的观点，即沙门氏菌效应蛋白必须从细菌细胞直接递送到宿主细胞中。
