Immunomodulatory activity of synthetic innate defence regulators (IDRs) (134.45)

Abstract

Abstract Cationic host defence (antimicrobial) peptides, e.g. cathelicidin LL-37, have a variety of immunomodulatory activities that favour the safe resolution of infections. We have studied novel synthetic cationic innate defence regulator peptides that are not directly antimicrobial but are anti-infective in vivo, due to modulation of innate immunity. A range of peptides derived from the small bovine peptide bactenecin were screened for immunomodulatory activities in vitro; e.g. promotion of chemokine production and suppression of pro-inflammatory cytokines. Since innate immunity is complex, involving >1,500 gene products, a systems biology approach was utilized to characterize peptide modulation of innate immunity, including analysis of receptors, signalling pathways, transcription factors and downstream genes. To permit visualization and bioinformatic analysis of complex events, an innate immunity database (www.innatedb.ca), a network visualization tool (Cerebral) and downstream analysis tools (e.g. pathway overrepresentation analysis) were developed and provided insight into how this selective modulation occurs. In vivo data indicate that these activities provide protection in animal model infections of Gram positive and Gram negative bacterial infections as well as severe malaria. Thus IDRs have great potential for use as novel anti-infective agents. Supported by Genome BC, FNIH and CIHR.