title: Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores.
abstract: 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.
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Tübingen, Eberhard-Karls-Universität, Tübingen, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hartmann
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Helena
authors.initials: H
authors.lastname: Wurz
authors.forename: Klaus
authors.initials: K
authors.lastname: Hantke
authors.forename: Alexander
authors.initials: A
authors.lastname: Rakin
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Matteoli
authors.forename: Erwin
authors.initials: E
authors.lastname: Bohn
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.forename: Jörn
authors.initials: J
authors.lastname: Karhausen
authors.forename: Diana
authors.initials: D
authors.lastname: Neumann
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Volkhard A J
authors.initials: VA
authors.lastname: Kempf
mesh_terms: 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
chemical_list: 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