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

H Hartmann, HK Eltzschig, H Wurz, K Hantke, A Rakin… - Gastroenterology, 2008 - Elsevier
H Hartmann, HK Eltzschig, H Wurz, K Hantke, A Rakin, AS Yazdi, G Matteoli, E Bohn…
Gastroenterology, 2008Elsevier
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 …
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-1α 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-1α 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.
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