Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada.
Front Immunol. 2019 May 7;10:928. doi: 10.3389/fimmu.2019.00928. eCollection 2019.
Numerous bacterial pathogens infect the mammalian host by initially associating with epithelial cells that line the intestinal lumen. Recent work has revealed that commensal bacteria that reside in the intestine promote defense against pathogenic infection, however whether the microbiota direct host pathways that alter pathogen adherence is not well-understood. Here, by comparing germ-free mice, we identify that the microbiota decrease bacterial pathogen adherence and dampen epithelial expression of the cell surface glycoprotein C-type lectin 2e (Clec2e). Functional studies revealed that overexpression of this lectin promotes adherence of intestinal bacterial pathogens to mammalian cells. Interestingly, microbiota-sensitive downregulation of Clec2e corresponds with decreased histone acetylation of the Clec2e gene in intestinal epithelial cells. Histone deacetylation and transcriptional regulation of Clec2e depends on expression and recruitment of the histone deacetylase HDAC3. Thus, commensal bacteria epigenetically instruct epithelial cells to decrease expression of a C-type lectin that promotes pathogen adherence, revealing a novel mechanism for how the microbiota promote innate defense against infection.
许多细菌病原体通过最初与肠道腔衬里的上皮细胞结合来感染哺乳动物宿主。最近的工作表明，肠道内的共生细菌促进了对病原体感染的防御，然而，微生物群是否直接指导宿主改变病原体黏附的途径还不是很清楚。在这里，通过比较无菌小鼠，我们发现微生物群减少了细菌病原体的黏附，并抑制了上皮细胞表面糖蛋白 C 型凝集素 2e（Clec2e）的表达。功能研究表明，这种凝集素的过表达促进了肠道细菌病原体与哺乳动物细胞的黏附。有趣的是，Clec2e 的微生物群敏感下调与肠道上皮细胞中 Clec2e 基因的组蛋白乙酰化减少相对应。Clec2e 的组蛋白去乙酰化和转录调控依赖于组蛋白去乙酰化酶 HDAC3 的表达和募集。因此，共生细菌通过表观遗传指令上皮细胞减少促进病原体黏附的 C 型凝集素的表达，揭示了微生物群促进先天防御感染的新机制。
