Activation of Hypoxia Inducible Factor 1 Is a General Phenomenon in Infections with Human Pathogens

Activation of Hypoxia Inducible Factor 1 Is a General Phenomenon in Infections with Human Pathogens

Nadine Werth, Christiane Beerlage, Christian Rosenberger, Amir S. Yazdi, Markus Edelmann, Amro Amr, Wanja Bernhardt, Christof von Eiff, Karsten Becker, Andrea Schäfer, Andreas Peschel, Volkhard A. J. Kempf

PLoS ONE 5(7): e11576. doi:10.1371/journal.pone.0011576


Background
Hypoxia inducible factor (HIF)-1 is the key transcriptional factor involved in the adaptation process of cells and organisms to hypoxia. Recent findings suggest that HIF-1 plays also a crucial role in inflammatory and infectious diseases.

Methodology/Principal Findings
Using patient skin biopsies, cell culture and murine infection models, HIF-1 activation was determined by immunohistochemistry, immunoblotting and reporter gene assays and was linked to cellular oxygen consumption. The course of a S. aureus peritonitis was determined upon pharmacological HIF-1 inhibition. Activation of HIF-1 was detectable (i) in all ex vivo in biopsies of patients suffering from skin infections, (ii) in vitro using cell culture infection models and (iii) in vivo using murine intravenous and peritoneal S. aureus infection models. HIF-1 activation by human pathogens was induced by oxygen-dependent mechanisms. Small colony variants (SCVs) of S. aureus known to cause chronic infections did not result in cellular hypoxia nor in HIF-1 activation. Pharmaceutical inhibition of HIF-1 activation resulted in increased survival rates of mice suffering from a S. aureus peritonitis.

Conclusions/Significance
Activation of HIF-1 is a general phenomenon in infections with human pathogenic bacteria, viruses, fungi and protozoa. HIF-1-regulated pathways might be an attractive target to modulate the course of life-threatening infections.

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