Staphylococcal sepsis - molecular basis, risk factors, and individual predisposition
The incidence and mortality of sepsis caused by Staphylococcus aureus and other Gram-positive bacteria has been increasing over the past two decades. Nevertheless, the molecular events leading to Gram-positive sepsis are still elusive and the options to avoid, predict the risk, and treat sepsis are very limited. Our current research is focused on staphylococcal pathogen-associated molecular patterns (PAMPs) such as lipoteichoic acid, peptidoglycan, and formyl peptides, the causative agents of sepsis, and we have analyzed S. aureus-induced transcription profiles in human cells in NGFN1. We plan to study the molecular events leading to Gram-positive sepsis and governing its outcome in a broad and interdisciplinary approach. Critical components in signal recognition and transduction (TLR2, NOD2, FPR,…) will be analysed in cell-based assays and in various models with transgenic mice (collaboration with E. Medina, B. Holzmann, T. Chakraborty). The potential of the anti-inflammatory S. aureus protein CHIPS, of PAMPspecific monoclonal antibodies, and of RNAi-based approaches will be evaluates. Possible correlations of occurrence and severity of sepsis with SNPs in critical human genes will be another major aspect of the project. Colonization of the anterior nares by S. aureus in approximately 37% of the human population represents a major risk factor for sepsis. In order to investigate the reasons for this predisposition, we aim to analyze transcription profiles in nasal epithelial cells upon challenge with S. aureus and evaluate the possible role of SNPs in the genes for defensin-like antimicrobial peptides, mediators of inflammation, adhesion molecules, and other critical components.
