Inhibition of Multidrug-resistant Acinetobacter baumannii by Nonviral Expression of hCAP-18 in a Bioengineered Human Skin Tissue

Abstract

When skin is compromised, a cascade of signals initiates the rapid repair of the epidermis to prevent fluid loss and provide defense against invading microbes. During this response, keratinocytes produce host defense peptides that have antimicrobial activity against a diverse set of pathogens. Using non-viral vectors we have genetically modified the novel, non-tumorigenic, pathogen-free human keratinocyte progenitor cell line (NIKS) to express the human cathelicidin host defense peptide in a tissue-specific manner. NIKS skin tissue that expresses elevated levels of cathelicidin possesses key histological features of normal epidermis and displays enhanced antimicrobial activity against bacteria in vitro. Moreover, in an in vivo infected burn wound model, this tissue results in a two log reduction in a clinical isolate of multidrug-resistant Acinetobacter baumannii. Taken together, these results suggest this genetically engineered human tissue could be applied to burns and ulcers to counteract bacterial contamination and prevent infection.

Cathelicidin LL-37: A Multitask Antimicrobial Peptide

“…A complex array of responses in many immunocompetent cells upon LL-37 treatment may also provide a new option for immunomodulatory use of this molecule. As a result of its activity on keratinocytes, LL-37 may be used as a pleiotropic agent against infection and as a wound healing enhancer in situations such as severe burn wound or skin transplant (Thomas-Virnig et al 2009). This new path for LL-37 therapeutic intervention deserves future investigation.…”

Clinical Evaluation of NIKS-Based Bioengineered Skin Substitute Tissue in Complex Skin Defects: Phase I/IIa Clinical Trial Results

“…Using this approach, skin tissues engineered to produce enhanced levels of antimicrobial factors have already been created. 56 The ability to specifically target known deficiencies or obstacles that delay healing of complex skin defects presents an important new therapeutic option for the treatment of these life-threatening injuries.…”

Chimeric Human Skin Substitute Tissue: A Novel Treatment Option for the Delivery of Autologous Keratinocytes

“…17 The expression of wound healing factors from keratinocytes has traditionally required viral transduction, 18,19 an approach that yields a heterogeneous population with a broad range of exogenous protein expression levels. As demonstrated by the successful generation and utilization of NIKS GFP and the work of Thomas-Virnig et al, 20 NIKS progenitor cells are amenable to genetic engineering using nonviral means. It is anticipated that autologous cells could be interspersed within a background tissue designed to express and secrete any number of proteins targeting wound healing enhancement.…”