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Abstract
Salmonella enterica serovar Typhimurium (S.Tm) infections of cultured cell lines have given rise to the ruffle model for epithelial cell invasion. According to this model, the Type-Three-Secretion-System-1 (TTSS-1) effectors SopB, SopE and SopE2 drive an explosive actin nucleation cascade, resulting in large lamellipodia- and filopodia-containing ruffles and cooperative S.Tm uptake. However, cell line experiments poorly recapitulate many of the cell and tissue features encountered in the host’s gut mucosa. Here, we employed bacterial genetics and multiple imaging modalities to compare S.Tm invasion of cultured epithelial cell lines and the gut absorptive epithelium in vivo in mice. In contrast to the prevailing ruffle-model, we find that absorptive epithelial cell entry in the mouse gut occurs through “discreet-invasion”. This distinct entry mode requires the conserved TTSS-1 effector SipA, involves modest elongation of local microvilli in the absence of expansive ruffles, and does not favor cooperative invasion. Discreet-invasion preferentially targets apicolateral hot spots at cell–cell junctions and shows strong dependence on local cell neighborhood. This proof-of-principle evidence challenges the current model for how S.Tm can enter gut absorptive epithelial cells in their intact in vivo context.
Highlights
Pathogenic Enterobacteriaceae, e.g. Salmonella, Shigella, and Escherichia species, cause >600 million cases of intestinal disease annually [1]
More than two decades of research have resulted in a detailed model for how S.Tm invades gut epithelial cells through effector triggering of large Rho-GTPasedependent actin ruffles
SopBEE2 activate a cohort of Rho- and Arf family GTPases, resulting in WAVE-regulatory complex (WRC) and Arp2/3-dependent actin nucleation, and the induction of large lamellipodia- and filopodia-containing membrane ruffles for bacterial uptake [8,9,14,16,17] (SopBEE2 hereafter referred to as “ruffle-inducers”)
Summary
Pathogenic Enterobacteriaceae, e.g. Salmonella, Shigella, and Escherichia species, cause >600 million cases of intestinal disease annually [1]. SopB carries a lipid phosphatase activity that alters the phosphatidylinositol-phosphate (PIP) composition of the plasma membrane inner leaflet [13]. This indirectly recruits multiple host factors, including Rho-GTPases and their activating Guanine nucleotide Exchange Factors (GEFs) to sites of bacterial docking [14,15]. SopBEE2 activate a cohort of Rho- and Arf family GTPases, resulting in WAVE-regulatory complex (WRC) and Arp2/3-dependent actin nucleation, and the induction of large lamellipodia- and filopodia-containing membrane ruffles for bacterial uptake [8,9,14,16,17] (SopBEE2 hereafter referred to as “ruffle-inducers”). The ruffles fuel macropinocytic uptake of bystander bacteria–a phenomenon referred to as cooperative invasion [5,18,19]
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