Role of the transcription factor HIF-1alpha in the formation of phagocyte extracellular traps.

• Applicant: Professorin Dr. Maren von Köckritz-Blickwede
• Subject Area: Veterinary Medical Science ; Biochemistry ; Cell Biology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 231062742

The hypoxia-inducible transcription factor (HIF-1alpha) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. There is increasing evidence, that HIF-1alpha is activated after exposure of host cells to microbial pathogens and supports the bactericidal activity of phagocytes. HIF-1alpha-agonists that are able to activate bactericidal mechanisms of host immune cells could conceivably be used alongside conventional antibiotics to function effectively against drug-resistant bacteria such as methicillin resistant Staphylococcus aureus (MRSA). However, the detailed cellular mechanisms of the HIF-1alpha-mediated bactericidal activity of phagocytes are still not entirely clear. Own preliminary data show that boosting of HIF-1alpha induces the formation of antimicrobial phagocyte extracellular traps (PETs) by mast cells and neutrophils, which has been recently recognized as a novel and important mechanism of the host immune response against infections. The aim of this study is (i) to identify host cells that release PETs in response to HIF-1alpha gene regulation during infection and/or hypoxia, (ii) to study the mechanisms of a HIF-1alpha-mediated formation of PETs and (iii) to evaluate the role of HIF-1alpha-mediated PET-formation against MRSA infections in vivo. This new knowledge will have significant implications for understanding the HIF-1alpha-mediated immune response as a novel target against drug-resistant bacterial infections.

• DFG Programme: Research Grants