Abstract
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.
Highlights
Infections of the gastrointestinal tract are a major cause of morbidity and mortality worldwide
Our data indicate that the microbiota can promote epithelial defense by epigenetically suppressing C-type lectin 2e (Clec2e)-mediated pathogen adherence
Previous studies have focused on investigating how the microbiota impact immune cell activation and antibacterial immunity [11, 47, 48], we observed very early susceptibility to C. rodentium infection in GF mice suggesting an important role for innate responses
Summary
Infections of the gastrointestinal tract are a major cause of morbidity and mortality worldwide. In addition to local intestinal infections, the gastrointestinal tract is the initial site of adhesion and entry for several pathogens that disseminate to cause systemic disease [3]. In order to establish disease, pathogens can interact with host cells by expressing adhesin molecules which recognize various components such as extracellular matrix proteins, integral membrane adhesion receptors, and cell membrane associated glycoproteins [4]. These interactions between bacterial pathogens and host cells are critical for initiating infection, and direct tissue tropism, species specificity, and host susceptibility to infection [4,5,6,7]. Understanding how pathogenic adherence is mediated is critical for directing effective approaches that prevent and treat enteric infections
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