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Infection and Immunity, October 2005, p. 6771-6781, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6771-6781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Keratinocyte Production of Cathelicidin Provides Direct Activity against Bacterial Skin Pathogens

Marissa H. Braff,1 Mohamed Zaiou,2 Joshua Fierer,1,3 Victor Nizet,4 and Richard L. Gallo1,3,4*

Department of Medicine,1 Department of Pediatrics, University of California, San Diego,4 Veterans Affairs Medical Center, San Diego, California,3 School of Pharmacy, l'Université Henri Poincaré, Nancy, France2

Received 25 April 2005/ Returned for modification 17 May 2005/ Accepted 2 June 2005

Immune defense at an interface with the external environment reflects the functions of physical and chemical barriers provided by epithelial and immune cells. Resident epithelial cells, such as keratinocytes, produce numerous peptides with direct antimicrobial activity but also provide a physical barrier against invading pathogens and signal the recruitment of circulating immune cells, such as neutrophils. Antimicrobial peptides such as cathelicidin are produced constitutively by neutrophils and are inducible in keratinocytes in response to infection. The multiplicity of antimicrobial peptides and their cellular sources has resulted in an incomplete understanding of the role of cathelicidin production by epithelial cells in cutaneous immune defense. Therefore, this study sought to evaluate keratinocyte antimicrobial activity and the potential contribution of keratinocyte cathelicidin to host protection against two leading human skin pathogens. Wild-type mice and those with a targeted deletion of the cathelicidin gene, Cnlp, were rendered neutropenic prior to cutaneous infection. Interestingly, Cnlp-deficient mice remained more susceptible to group A streptococcus infection than mice with Cnlp intact, suggesting the involvement of epithelial cell-derived cathelicidin in host immune defense. Keratinocytes were then isolated in culture and found to inhibit the growth of Staphylococcus aureus, an effect that was partially dependent on their ability to synthesize and activate cathelicidin. Further, lentivirus-mediated delivery of activated human cathelicidin enhanced keratinocyte antimicrobial activity. Combined, these data illustrate the potential contribution of keratinocyte cathelicidin to the innate immune defense of skin against bacterial pathogens and highlight the need to consider epithelial antimicrobial function in the diagnosis and therapy of skin infection.

* Corresponding author. Mailing address: 3350 La Jolla Village Drive, Mail Code 151, San Diego, CA 92161. Phone: (858) 552-8585. Fax: (858) 552-7436. E-mail: rgallo{at}vapop.ucsd.edu.

Editor: A. D. O'Brien

Infection and Immunity, October 2005, p. 6771-6781, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6771-6781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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