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

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

doi:10.1371/journal.pone.0011576

Abstract

BackgroundHypoxia 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 FindingsUsing 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/SignificanceActivation 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.

Highlights

Mammalian cells adapt to oxygen deprivation by the activation of hypoxia inducible factor (HIF)-1, the key transcription factor during hypoxia
In all cutaneous infections [here: infections with S. aureus (Fig. 1B), coinfection with S. agalactiae and S. aureus (Fig. 1C), coinfection with Acinetobacter baumanii and E. coli (Fig. 1D), infections with Borellia burgdorferi (Fig. 1E), Varicella zoster virus (Fig. 1F), Human Herpes Virus-8 (Fig. 1G), Tinea rubrum (Fig. 1H,I), C. albicans (Fig. 1J) and Leishmania donovani (Fig. 1K,L)] a strong nuclear Hypoxia inducible factor (HIF)-1a signal was detected in keratinocytes, dermal capillaries, neutrophils, dermal lymphocytes and macrophages and sub-corneal neutrophils
We demonstrate that HIF-1 activation in infections with human pathogenic microorganisms is a general phenomenon not restricted to certain pathogens

Summary

Introduction

Mammalian cells adapt to oxygen deprivation by the activation of hypoxia inducible factor (HIF)-1, the key transcription factor during hypoxia. The expression of hypoxia-inducible genes involved in angiogenesis [e.g., vascular endothelial growth factor (VEGF)], glycolysis [e.g., hexokinase (HK)], proliferation and survival [e.g., adrenomedullin (ADM)] and erythropoiesis (e.g., erythropoietin) is transcriptionally regulated [1,2]. The key mechanism involved in HIF-1 activation has been identified to require inhibition of the enzymatic activity of ‘‘prolyl hydroxylase domain’’-containing proteins (PHDs) during hypoxia. PHDs mediate hydroxylation of the prolyl residues Pro402 and Pro564 of the HIF-1a subunit which results in the binding to the von-Hippel-Lindau protein and subsequent proteasomal degradation under normoxic conditions. 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 a crucial role in inflammatory and infectious diseases

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Conclusion