Published Online
on February 21, 2005

A more recent version of this article appeared on March 1, 2005

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Submitted on July 14, 2004
Revised on September 30, 2004
Accepted on October 28, 2004

Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis. Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections

Volkhard A.J. Kempf MD^*, Maria Lebiedziejewski , Kari Alitalo MD, PhD, Joo-Hee Wälzlein , Urs Ehehalt , Jeannette Fiebig , Stephan Huber PhD, Burkhardt Schütt PhD, Christian A. Sander MD, Steffen Müller PhD, Guntram Grassl PhD, Amir, S. Yazdi MD, Bernhard Brehm MD, and Ingo B. Autenrieth MD

From the Institut für Medizinische Mikrobiologie und Hygiene, Eberhard-Karls Universität, Tübingen, Germany (V.A.J.K., M.L., J.W., U.E., J.F., S.M., G.G., I.B.A.); Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (K.A.); Institute of Physiology, Tübingen, Germany (S.H.); Universitätsklinik für Kinderheilkunde und Jugendmedizin, Tübingen, Germany (B.S.); Klinik für Dermatologie und Allergologie, Ludwig Maximilians Universität, Munich, Germany (C.A.S., A.S.Y.); and Medizinische Universitätsklinik III, Tübingen, Germany (B.B.).

^* To whom correspondence should be addressed. E-mail: volkhard.kempf{at}med.uni-tuebingen.de.

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.

Key words: angiomatosis, bacillary • Bartonella henselae • angiogenesis • HIF-1 protein • hypoxia

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