Author:

Keywords:

Animals, Caco-2 Cells, Cell Hypoxia, Disease Models, Animal, Endothelial Cells, Enterobacter aerogenes, Enterobacteriaceae, Epithelial Cells, Female, Gene Expression Regulation, Hela Cells, Humans, Hydroxamic Acids, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Oxygen, Peyer's Patches, Phenols, Procollagen-Proline Dioxygenase, Salmonella enterica, Siderophores, Thiazoles, Time Factors, Transcriptional Activation, Up-Regulation, Yersinia Infections, Yersinia enterocolitica, Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, INDUCIBLE FACTOR-I, ENDOTHELIAL GROWTH-FACTOR, YERSINIA-ENTEROCOLITICA, GENE-EXPRESSION, TRANSPORT GENES, NITRIC-OXIDE, HIF-1-ALPHA, VIRULENCE, IRON, PATHOGENICITY, HeLa Cells, 1103 Clinical Sciences, 1109 Neurosciences, 1114 Paediatrics and Reproductive Medicine, 3202 Clinical sciences, 3210 Nutrition and dietetics

Abstract:

BACKGROUND & AIMS: Hypoxia inducible factor-1 (HIF-1) is the key transcriptional regulator during adaptation to hypoxia. Recent studies provide evidence for HIF-1 activation during bacterial infections. However, molecular details of how bacteria activate HIF-1 remain unclear. Here, we pursued the role of bacterial siderophores in HIF-1 activation during infection with Enterobacteriaceae. METHODS: In vivo, HIF-1 activation and HIF-1-dependent gene induction in Peyer's patches were analyzed after orogastric infection with Yersinia enterocolitica. The course of an orogastric Y enterocolitica infection was determined using mice with a deletion of HIF-1alpha in the intestine. In vitro, the mechanism of HIF-1 activation was analyzed in infections with Y enterocolitica, Salmonella enterica subsp enterica, and Enterobacter aerogenes. RESULTS: Infection of mice with Y enterocolitica led to functional activation of HIF-1 in Peyer's patches. Because mice with deletion of HIF-1alpha in the intestinal epithelium showed a significantly higher susceptibility to orogastric Y enterocolitica infections, bacterial HIF-1 activation appears to represent a host defense mechanism. Additional studies with Y enterocolitica, S enterica subsp enterica, or E aerogenes, and, moreover, application of their siderophores (yersiniabactin, salmochelin, aerobactin) caused a robust, dose-dependent HIF-1 response in human epithelia and endothelia, independent of cellular hypoxia. HIF-1 activation occurs most likely because of inhibition of prolylhydroxylase activity and is abolished upon infection with siderophore uptake deficient bacteria. CONCLUSIONS: Taken together, this study reveals what we believe to be a previously unrecognized role of bacterial siderophores for hypoxia-independent activation of HIF-1 during infection with human pathogenic bacteria.