Hiding within the Human Host - Persistence and Resistance Strategies by Gram-positive Bacteria in Severe Necrotizing Skin and Soft Tissue Infections

• Applicant: Professor Dr. Nikolai Siemens
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407176682

This project focuses on severe acute infections caused by Gram-positive bacteria: group A and G streptococci (GAS; GGS) and methicillin-resistant Staphylococcus aureus (MRSA). These microorganisms are associated with a variety of diseases ranging from superficial skin and throat infections to life-threatening sepsis, toxic shock syndrome and necrotizing soft tissue infections (NSTIs). The latter are rapidly progressing infections associated with high mortality and morbidity despite prompt antibiotics and intensive care. Our recent findings suggest that there is (i) a substantial biofilm formation in the soft tissue and (ii) genetic and phenotypic adaptation of the bacteria during NSTIs. This opens up a novel line of research focusing on persistence and resistance phenotypes at the tissue site. We believe that bacterial persistence represents a key determinant of disease severity resulting in a significant reservoir associated with a sustained virulence factors production and tissue pathology. NSTIs often require extensive tissue debridement or even amputation, and they are associated with substantial mortality. These infections represent an increasing health problem globally. We will apply tissue engineering to generate in vitro skin, which will allow us to study bacterial persistence/resistance phenotypes at the tissue site including phenotypic switches of the bacteria and biofilm formation, virtually unexplored topics in acute NSTIs. In addition, we will conduct comprehensive analyses of bacterial load in the large tissue biopsy material and relate them to the patient records (treatment, outcome etc.). Further, we will identify (i) potential virulence mechanisms and therapy targets and (ii) host pathways contributing to the severity of infection. The data on severe NSTIs is sparse and requires more investigations. The expected impact of the proposed project is broad and involves several aspects, including (i) novel insight into the pathophysiology of severe skin and soft tissue infections and (ii) a novel experimental system superior for studies of bacterial resistance phenotypes in tissue.

• DFG Programme: Research Grants