Imaging Innate Immunity of Staphylococcal Infectio.. (PSMS-IN-INFLAMMATION)
Imaging Innate Immunity of Staphylococcal Infections
Start date: Apr 9, 2014,
End date: Apr 8, 2017
"Staphylococcus aureus community-acquired (CA)-MRSA strains are highly virulent and can cause infections in otherwise healthy individuals and are a leading cause of death worldwide. Innate immunity is our primary defense against invading staphylococci. Blood-neutrophils migrate to the site of infection where they, in concert with the complement system, engulf and kill bacteria in a process called phagocytosis. Especially CA-MRSA strains seem to be very efficient in circumventing this neutrophil killing. Interestingly, only a relative small number of virulence factors have been associated with CA-MRSA, one of which are the phenol soluble modulins (PSMs). In vivo models of experimental infection with PSM-mutants have shown a critical role for PSMs in skin and soft tissue infections. PSMs are small alpha-helical peptides which have two distinct functions on the immune system, in vitro PSMs can attract neutrophils in the nanomolar range, whereas in the micromolar range they are cytolytic for neutrophils. Recent publications suggests that these two functions complement each other for full staphylococcal virulence, although it seems counter-intuitive for S. aureus to actively attract its mortal enemy: the neutrophil. To make matters even more complicated PSMs are functionally inactivated by host serum lipoproteins, most efficiently by high density lipoprotein (HDL). The goal of this research proposal is to determine the mechanism of action for PSMs in staphylococcal disease. To this end, I will use genomic and proteomic approaches combined with cutting edge in vivo spinning-disk confocal microscopy, to dissect the functions of PSMs in host-staphylococcal interactions in; 1) neutrophil recruitment, 2) neutrophil lysis 3) HDL neutralization and liver pathology, 4) Evasion of PSM-recognition by FLIPR-L"
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