Staphylococcal scalded skin syndrome, SSSS, is a disease primarily of the young and immunocompromised that is rarely seen in healthy adults. SSSS is characterized by specific exfoliation of the upper epidermis in the stratum granulosum of the skin at a site distal to a focus of infection with exfoliative toxin (ET) producing Staphylococcus aureus. The exact mechanism of the relative protection of adults or susceptibility of newborns is not known. In an animal model these skin manifestations result from the injection of one of two species-specific exfoliative toxins, ETA or ETB. The mechanism by which these toxins result in exfoliation is now assumed to involve cleavage of desmoglein 1 (Dsgl), a desmosomal protein member of the cadherin family of cell adhesion molecules, by a unique serine protease activity of the exfoliative toxins. Cleavage of this protein fits the clinical picture of SSSS as it is primarily expressed at this layer of this skin. Our hypothesis is that characteristics of the interaction between the exfoliative toxins of S. aureus and their target desmoglein 1 explain the species, target and age specificity of these toxins as well as contribute to the pathogenicity of these bacteria. We propose in this study to use molecular techniques to characterize the interaction between the toxin, ETA and the target, Dsgl of humans and mice. The goal is to determine the domains or amino acids of Dsgl needed for recognition and cleavage by ETA and the domains or amino acids of ETA responsible for target binding and localization to the skin. Results from these analyses will provide insight into the mechanism for the age and species specificity of this unique serine protease. We further propose to develop an animal model of staphylococcal impetigo to address the role of the exfoliative toxins in pathogenesis of these bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048882-05
Application #
7241609
Study Section
Special Emphasis Panel (ZRG1-GMA-1 (01))
Program Officer
Lapham, Cheryl K
Project Start
2003-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$257,133
Indirect Cost
Name
University of Miami School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Katz, J N; Losina, E; Lohmander, L S (2015) OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of surgical interventions for osteoarthritis. Osteoarthritis Cartilage 23:798-802
Mertz, Patricia M; Cardenas, Tatiana C P; Snyder, Richard V et al. (2007) Staphylococcus aureus virulence factors associated with infected skin lesions: influence on the local immune response. Arch Dermatol 143:1259-63