Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores.
OBJECTIVE
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.
Hartmann
Hanna
H
Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Tübingen, Eberhard-Karls-Universität, Tübingen, Germany.
Eltzschig
Holger K
HK
Wurz
Helena
H
Hantke
Klaus
K
Rakin
Alexander
A
Yazdi
Amir S
AS
Matteoli
Gianluca
G
Bohn
Erwin
E
Autenrieth
Ingo B
IB
Karhausen
Jörn
J
Neumann
Diana
D
Colgan
Sean P
SP
Kempf
Volkhard A J
VA
D000818:Animals; D018938:Caco-2 Cells; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology; D021902:Enterobacter aerogenes / Q000378:metabolism; D004755:Enterobacteriaceae / Q000378:metabolism* / Q000472:pathogenicity; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D010581:Peyer's Patches / Q000378:metabolism* / Q000382:microbiology; D010636:Phenols / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D019779:Salmonella enterica / Q000378:metabolism; D017262:Siderophores / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D015009:Yersinia Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D015008:Yersinia enterocolitica / Q000378:metabolism
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010636:Phenols; D017262:Siderophores; D013844:Thiazoles; C104398:yersiniabactin; C031819:aerobactin; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen