Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections.
Kempf, Volkhard A.J. MD *; Lebiedziejewski, Maria *; Alitalo, Kari MD, PhD *; Walzlein, Joo-Hee; Ehehalt, Urs; Fiebig, Jeannette; Huber, Stephan PhD; Schutt, Burkhardt PhD; Sander, Christian A. MD; Muller, Steffen PhD; Grassl, Guntram PhD; Yazdi, Amir S. MD; Brehm, Bernhard MD; Autenrieth, Ingo B. MD
111(8):1054-1062, March 1, 2005.
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Background-: Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown.
Methods and Results-: Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae-infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae-induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1-specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of B henselae did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells.
Conclusions-: B henselae induces a proangiogenic host cell response via HIF-1. Our data provide for the first time evidence that HIF-1 may play a role in bacterial infections.
(C) 2005 American Heart Association, Inc.