Exfoliative toxin A (ETA) secreted by Staphylococcus aureus causes destruction of human epidermis in bullous impetigo and Staphylcoccal Scalded Skin Syndrome (SSSS), which renders victims vulnerable to life-threatening infections and dehydration. Desmosomes are crucial for cell:cell adhesion in tissues enduring stress, such as the epidermis. These protein complexes anchor intermediate filaments to celhcell junctions, providing the mechanical strength necessary for the skin to serve as the body's first line of defense against environmental insults. Previous work has shown that ETA cleaves desmoglein 1 (Dsg1), a desmosome component and the predominant cadherin of the superficial epidermis. The proposed research will determine the specific molecular consequences of Dsg1 cleavage by ETA that contribute to SSSS. In particular, the toxin's effects on trafficking of and interactions among desmosomal components will be investigated as mechanisms reducing adhesion in keratinocytes; as well, a decoy Dsg1 ectodomain will be evaluated as an ETA inhibitor in vitro and in epidermal equivalents. The results will provide a more complete understanding of SSSS pathogenesis and will identify novel therapeutic targets for treatment of a toxin-mediated disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30ES014990-03
Application #
7485060
Study Section
Special Emphasis Panel (ZRG1-F10-H (21))
Program Officer
Humble, Michael C
Project Start
2006-09-01
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$28,927
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Hobbs, Ryan P; Amargo, Evangeline V; Somasundaram, Agila et al. (2011) The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signaling. FASEB J 25:990-1001
Simpson, Cory L; Kojima, Shin-ichiro; Cooper-Whitehair, Victoria et al. (2010) Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin desmoglein 1: implications for exfoliative toxin-mediated skin blistering. Am J Pathol 177:2921-37
Simpson, Cory L; Kojima, Shin-ichiro; Getsios, Spiro (2010) RNA interference in keratinocytes and an organotypic model of human epidermis. Methods Mol Biol 585:127-46
Getsios, Spiro; Simpson, Cory L; Kojima, Shin-ichiro et al. (2009) Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis. J Cell Biol 185:1243-58
Green, Kathleen J; Simpson, Cory L (2007) Desmosomes: new perspectives on a classic. J Invest Dermatol 127:2499-515