Novel evasion strategies of Staphylococcus aureus against the human innate immune response

Koch, Tina Katrin GND

There is an ongoing competition between the human host and pathogenic microbes. The immune system, especially the immediately acting innate response, recognizes pathogens, prevents their spreading, and eliminates them. By contrast, certain microbes have developed sophisticated strategies to evade and suppress the host immune response. This thesis focuses on the functions of the plasma proteins apolipoprotein E (apoE)and plasmin in the interactions between the human host and the pathogen Staphylococcus aureus. Here, it is shown that antimicrobial peptides (AMPs) were generated from apoE upon cleavage by neutrophil elastase. The bactericidal activity was located to the heparin-binding site of the LDL-receptor-binding domain of apoE (SHL14). Full-length apoE had no antibacterial, but opsonic activity. Additionally, a new function of plasmin is reported. The serine protease degraded the AMPs C3a and SHL14. Thereby plasmin terminated bactericidal activity and may facilitate clearance of no longer needed effector molecules. Plasminogen, the precursor of plasmin, is bound by S. aureus. Here, a novel type of plasminogen-binding proteins, unique for S. aureus, is shown. Sbi and Efb recruited plasminogen together with the complement component C3. Plasminogen, fixed in these complexes, remained accessible to its activators uPa and staphylokinase. In the presence of Sbi or Efb, plasmin-mediated degradation of C3(C3b) was accelerated, likely due to conformational changes in C3(C3b). Thus, S. aureus efficiently inactivates complement activity. Plasmin and the metalloprotease aureolysin were also used by S. aureus to degrade the AMP SHL14 and inactivate the anti-opsonic activity of apoE. Taken together, apoE and plasmin have different functions in the interactions between host and pathogen. ApoE is part of the immune response against S. aureus and thus degraded by the pathogen. By contrast, plasmin restricts immune reactions and its activity is therefore exploited by S. aureus.



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