PROJECT SUMMARY (See instructions): This project has sought to understand the functions of the cathelicidin family of antimicrobial peptides in mammalian immunity. Cathelicidins are an evolutionarily conserved gene family, with orthologous genes present in several species. Conservation between family members resides primarily in the amino-terminal precursor domain. The carboxy-terminal peptide domain has potent immunological activity, acting as an endogenous direct antimicrobial that kills some pathogens. Our previous work has shown that this activity is essential for resistance to invasive bacterial infection by S. aureus and Group A Streptococcus and associated with several human inflammatory diseases. However, our group and others have found that some of the human disease associations with cathelicidin are likely not a consequence of its antibiotic activity but rather due to its immune activating activity. Several important observations prior to year 1 suggested that the human cathelicidin peptide LL37 will amplify inflammation by presenting nucleic acids to cytosolic receptors. We termed this process " innate immune vetting " .