Abstract
The cellular invasion machinery of the enteric pathogen Salmonella consists of a type III secretion system (T3SS) with injectable virulence factors that induce uptake by macropinocytosis. Salmonella invasion at the apical surface of intestinal epithelial cells is inefficient, presumably because of a glycosylated barrier formed by transmembrane mucins that prevents T3SS contact with host cells. We observed that Salmonella is capable of apical invasion of intestinal epithelial cells that express the transmembrane mucin MUC1. Knockout of MUC1 in HT29-MTX cells or removal of MUC1 sialic acids by neuraminidase treatment reduced Salmonella apical invasion but did not affect lateral invasion that is not hampered by a defensive barrier. A Salmonella deletion strain lacking the SiiE giant adhesin was unable to invade intestinal epithelial cells through MUC1. SiiE-positive Salmonella closely associated with the MUC1 layer at the apical surface, but invaded Salmonella were negative for the adhesin. Our findings uncover that the transmembrane mucin MUC1 is required for Salmonella SiiE-mediated entry of enterocytes via the apical route.
Highlights
In the gastrointestinal tract, the luminal microbiota is separated from the underlying epithelial cells by a complex system collectively called the mucus layer
The apical surface of intestinal epithelial cells is covered with a defensive barrier of large glycosylated transmembrane mucins
We show for the first time that MUC1, one of the intestinal apical transmembrane mucins, facilitates Salmonella invasion
Summary
The luminal microbiota is separated from the underlying epithelial cells by a complex system collectively called the mucus layer. The mucus layer consists of soluble gel-forming mucins such as MUC2 and MUC5A that are secreted by Goblet cells, IgA antibodies, host defense peptides, and other anti-microbial components [1]. Another component of the mucus layer are transmembrane mucins, which are large glycoproteins that are expressed on the apical surface of enterocytes and Goblet cells. Transmembrane mucins have a highly glycosylated extracellular domain with potential barrier function, a transmembrane domain and a cytoplasmic tail that links to signaling pathways [3]. MUC1 is the most extensively studied transmembrane mucin and is highly expressed at mucosal surfaces including the stomach and the intestinal tract [4,5]. The human and mouse MUC1 extracellular domains share less than 40% homology while the transmembrane domain and cytoplasmic tail are highly conserved [9]
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