Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores.

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.

• Authors: Hanna Hartmann, Holger K Eltzschig, Helena Wurz, Klaus Hantke, Alexander Rakin, Amir S Yazdi, Gianluca Matteoli, Erwin Bohn, Ingo B Autenrieth, Jörn Karhausen, Diana Neumann, Sean P Colgan, Volkhard A J Kempf
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 3 Pg. 756-67 (Mar 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18325389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hif1a protein, mouse
• Hydroxamic Acids
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phenols
• Siderophores
• Thiazoles
• yersiniabactin
• aerobactin
• Procollagen-Proline Dioxygenase
• Oxygen

Topics

• Animals
• Caco-2 Cells
• Cell Hypoxia
• Disease Models, Animal
• Endothelial Cells (metabolism, microbiology)
• Enterobacter aerogenes (metabolism)
• Enterobacteriaceae (metabolism, pathogenicity)
• Epithelial Cells (metabolism, microbiology)
• Female
• Gene Expression Regulation
• HeLa Cells
• Humans
• Hydroxamic Acids (metabolism)
• Hydroxylation
• Hypoxia-Inducible Factor 1, alpha Subunit (deficiency, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Oxygen (metabolism)
• Peyer's Patches (metabolism, microbiology)
• Phenols (metabolism)
• Procollagen-Proline Dioxygenase (metabolism)
• Salmonella enterica (metabolism)
• Siderophores (metabolism)
• Thiazoles (metabolism)
• Time Factors
• Transcriptional Activation
• Up-Regulation
• Yersinia Infections (genetics, metabolism, microbiology)
• Yersinia enterocolitica (metabolism)