Helicobacter pylori PqqE is a new virulence factor that cleaves junctional adhesion molecule A and disrupts gastric epithelial integrity.

Helicobacter pylori infects approximately half of the world's population and is the strongest risk factor for peptic ulcer disease and gastric cancer, representing a major global health concern. H. pylori persistently colonizes the gastric epithelium, where it subverts the highly organized structures that maintain epithelial integrity. Here, a unique strategy used by H. pylori to disrupt the gastric epithelial junctional adhesion molecule-A (JAM-A) is disclosed, using various experimental models that include gastric cell lines, primary human gastric cells, and biopsy specimens of infected and non-infected individuals. H. pylori preferentially cleaves the cytoplasmic domain of JAM-A at Alanine 285. Cells stably transfected with full-length JAM-A or JAM-A lacking the cleaved sequence are used in a range of functional assays, which demonstrate that the H. pylori cleaved region is critical to the maintenance of the epithelial barrier and of cell-cell adhesion. Notably, by combining chromatography techniques and mass spectrometry, PqqE (HP1012) is purified and identified as the H. pylori virulence factor that cleaves JAM-A, uncovering a previously unreported function for this bacterial protease. These findings propose a novel mechanism for H. pylori to disrupt epithelial integrity and functions, breaking new ground in the understanding of the pathogenesis of this highly prevalent and clinically relevant infection.

Kidney histologic alterations in α-Galactosidase-deficient mice.

Fabry disease is a rare X-linked disorder caused by mutations in the α-galactosidase gene (GLA), the resultant deficiency of lysosomal α-galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy.

Kidney biopsy findings in heterozygous Fabry disease females with early nephropathy.

Fabry disease is an X-linked glycosphingolipidosis caused by deficiency of alpha-galactosidase. Progressive chronic kidney disease (CKD) is a major cause of morbidity and mortality in males. Although 40% of heterozygous females may develop renal involvement, pathologic data on Fabry nephropathy in heterozygotes are scarce. We reviewed the kidney biopsies of four affected females who had normal to slightly sub-normal renal function, two of them with overt proteinuria. Chronic non-specific degenerative lesions and glycosphingolipid accumulation per cell type were semi-quantitatively assessed by light and electron microscopy. Cellular distribution of glycosphingolipid deposits was best assessed on semithin sections. Podocyte effacement was seen only in proteinuric patients. Combined analysis of our data with those of two earlier series showed that glomerular sclerosis and tubulointerstitial fibrosis are predictors of proteinuria and CKD stage. There was no histopathological evidence supporting a major role of vascular damage in the early pathogenesis of Fabry nephropathy in females.