Molecular Mechanisms

Molecular mechanisms leading to formation of extracellular traps (ETs)

The molecular mechanisms leading to the formation of antimicrobial ETs, are still not entirely understood. Accumulated evidence has indicated that highly interactive molecular networks are involved in this process. However, the detailed signalling events such as involvement of specific transcriptional regulators are not known.

A characteristic feature of the tissue environment during staphylococcal infections is hypoxia. Whereas in healthy tissues oxygen tension is generally 20-70 mm Hg (i.e. 2.5-9% oxygen), much lower levels (<1% oxygen) have been described in wounds and necrotic tissue foci. The adaptive response of mammalian cells to the stress of oxygen depletion during infection is mainly coordinated by the action of hypoxia-inducible transcription factor 1 (HIF-1α). Under hypoxic conditions, HIF-1α regulates the transcription of hundreds of genes in a cell-type specific manner. The battery of target genes of HIF-1α varies considerably from one cell type to another and is able to mediate different cell-type specific physiological processes. Recently, it has been shown that HIF-1a modulates the bactericidal capacity of phagocytes such as macrophages and neutrophils by regulating the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNFa.

The role of HIF-1α in phagocyte function and the formation of ETs will be investigated in cooperation with Victor Nizet, UCSD La Jolla, California, Randall Johnsson, UCSD La Jolla, California, Annelies Zinkernagel from Universitätsspital Zürich, Switzerland, and with Eva Medina and Oliver Goldmann from the Helmholtz-Center in Braunschweig, Germany.