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TRR 34:  Pathophysiology of Staphylococci in the Post-Genome-Era

Subject Area Medicine
Biology
Term from 2006 to 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 16524344
 
Final Report Year 2018

Final Report Abstract

Staphylococcus aureus is a dangerous pathogen, a leading cause of bacterial infection in hospitals and in the community world-wide. The microorganism is a prominent example of the crisis of antibiotic resistance, one of the major threats to health in the 21st century. Despite extensive efforts there is no effective anti-S. aureus vaccine. At the same time, S. aureus is a fascinating model organism for the study of host-pathogen interaction. Each of us is exposed to the bacteria, often within the first hours of life. The encounters with this versatile microorganism are multi-facetted ranging from rapid elimination or symptomless colonisation through mild skin infections to life threatening disease. S. aureus is equipped with an impressive assortment of fitness and virulence factors, including a wide variety of immune evasive compounds. Intricate regulation networks enable the bacteria to withstand hostile environmental conditions, such as nutrient limitation, oxidative stress or anaerobic conditions. So, they can adapt to very different niches in their host and in the environment, a basis of their success. The overarching objective of the CRC-TRR34 was a better understanding of the pathophysiology of S. aureus. Complete genome sequences of S. aureus and its human host had become available a few years before the consortium took up its work. The researchers could therefore rely on comprehensive analysis of transcriptional profiles, proteins, and metabolites, and combine these OMICs approaches with proven methods to elucidate mechanisms and causal relationships. This strategy was very fruitful. As a foundation, a (almost) complete quantitative inventory of the S. aureus proteins was generated in a laboratory strain, comprising the intracellular proteins as well as cell wall-bound and extracellular factors. Next, the adaptation of the bacteria to numerous infection-relevant stress conditions was extensively characterized in cell cultures. Molecular signatures were defined, which help to reveal the conditions S. aureus encounters when confronting his host and the pathogen’s reactions to them. It turned out that the bacteria rely on similar adaptation mechanisms inside biofilms, after uptake into host cells, and under the influence of antibiotics. These processes are important in chronic S. aureus infections as they occur in the bone or around implants. Such infections are very difficult to treat, because some bacteria are not destroyed after ingestion by the host cells, but able to persist. Their adaptation mechanisms render them extremely resistant to the immune system and to antibiotics. The same applies to S. aureus in biofilms. In order to elucidate these interactions between the pathogen and the host, members of the CRC-TRR34 have used cell culture systems of increasing complexity, developed suitable infection models in animals, and conducted clinical investigations. Moreover, we now understand much better how S. aureus succeeds in permanently colonizing the human nose. The spatio-temporally finely tuned process is essentially determined by the structure of the wall teichoic acids in the bacterial cell wall, which bind to receptors on the host cell surface. Although the bacteria behave rather harmless there, the immune system has to spend significant resources throughout life to maintain equilibrium between the pathogen and its host. The CRC-TRR34 has also helped to dispel doubts about the adaptive immune system's ability to provide clinical protection against S. aureus. These had come up because the results of efforts to develop a vaccine against the sophisticated pathogen were disappointing. Meanwhile, international research has picked up in this area again. However, it was recognized that the immune response to S. aureus can also cause damage. The suspicion that S. aureus can trigger and sustain allergies was confirmed by the discovery of strong bacterial allergens. The clinical significance of this finding in chronic inflammation involving S. aureus must now be elucidated. In conclusion, during the 12 years of funding much could be achieved, more remains to be done. The scientists involved in the CRC-TRR34 are highly motivated to continue and further expand their cooperation established in the consortium and in its international networks.

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