Hypoxia-Inducible Factor 1-Regulated Lysyl Oxidase Is Involved in Staphylococcus aureus Abscess Formation

Abstract

ABSTRACTHypoxia-inducible factor 1 (HIF-1) is the key transcription factor involved in the adaptation of mammals to hypoxia and plays a crucial role in cancer angiogenesis. Recent evidence suggests a leading role for HIF-1 in various inflammatory and infectious diseases. Here we describe the role of HIF-1 inStaphylococcus aureusinfections by investigating the HIF-1-dependent host cell response. For this purpose, transcriptional profiling of HIF-1α-deficient HepG2 and control cells, both infected withStaphylococcus aureus, was performed. Four hours after infection, the expression of 190 genes, 24 of which were regulated via HIF-1, was influenced.LOX(encoding lysyl oxidase) was one of the upregulated genes with a potential impact on the course ofS. aureusinfection. LOX is an amine oxidase required for biosynthetic cross-linking of extracellular matrix components. LOX was upregulatedin vitroin different cell cultures infected withS. aureusand alsoin vivo, in kidney abscesses of mice intravenously infected withS. aureusand in clinical skin samples from patients withS. aureusinfections. Inhibition of LOX by β-aminopropionitrile (BAPN) did not affect the bacterial load in kidneys or blood but significantly influenced abscess morphology and collagenization. Our data provide evidence for a crucial role of HIF-1-regulated LOX in abscess formation.