Mouse Gastric Epithelial Cells Resist CagA Delivery by the Helicobacter pylori Type IV Secretion System

Abstract

The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ–Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer.

The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells

“…Given this, we next conducted an infection study of adult mice with cagA + H. pylori. However, we subsequently noticed that mouse gastric epithelial cells resist H. pylori-mediated CagA injection because of the incompatible interaction of H. pylori adhesin HopQ with mouse Ceacam proteins (49)(50)(51).…”

The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk

“… 168 Moreover, mouse gastric epithelial cells are resistant to the actions of CagA due to the inability of HopQ to bind to mouse CEACAMs. 169 The loss of Cag T4SS activity in vivo, combined with resistance of mouse cells to CagA activity, may account at least in part for the absence of gastric cancer or gastric ulceration in H. pylori -infected wild-type mice.…”

Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis

“…A recent study noted that the instability of the relationship between H. pylori HopQ and mouse CEACAMs may explain why the pathogenesis of infection in the stomach of rodents infected with CagA positive H. pylori strains occurs differently from infection by the same strain in humans. The authors also demonstrated that the presence of functional T4SS is associated with a time-dependent reduction in human CEACAM1 levels after CagA-positive H. pylori infection[ 54 ]. However, it is still unclear whether the instability of the HopQ–CEACAMs relationship favors the host or the bacterium, so more studies are needed to investigate the possibility of these interactions being beneficial in favor of the patient infected with H. pylori.…”