The polymorphonuclear granulocyte (neutrophil, PMN) commonly provides the first line of host defense against a variety of potentially pathogenic bacteria and fungi. For killing of ingested organisms, PMNs possess two antimicrobial systems which are distinguished by their reliance on molecular oxygen. Until recently, it was assumed that """"""""oxygen-independent"""""""" effector substances acted merely to backup the """"""""oxygen-dependent"""""""" mode of killing. Recent data suggest that (oxygen-independent) microbicidal lysosomal constituents play a greater role as antimicrobial agents than previously thought. In this regard, specific evidence has been provided by the observation that PMN killing of several organisms is relatively unaffected by anaerobiosis. Demonstration by several investigators that """"""""cationic proteins"""""""" from PMN granules possess microbicidal activity has led to the purification and characterization of a number of antimicrobial compounds. A group of ten (6 rabbit, 3 human, 1 guinea pig) structurally homologous peptides were recently purified and characterized by this investigator. Each member of this family was small (3000-4100 Daltons), arginine- and cystine-rich, and contained an invariant framework of eight conserved residues. The peptides had a broad antimicrobial spectrum that include bacteria, fungi, and certain enveloped viruses. Our goal is to elucidate the molecular basis for neutrophil peptide-mediated microbicidal effect. We propose to study peptide structure and function by 1) extending our ability to correlate structure and function through purification and characterization of analogous peptides from bovine neutrophils, 2) comparing the functional aspects of structurally defined peptides by determining their antimicrobial potency and spectrum, 3) determining the disulfide structures of selected neutrophil peptides, 4) identifying essential structural and/or functional domains by site-specific modifications and the use of synthetic peptide probes. These four aims are intended to provide a complimmentary approach to the dissection of peptide-mediated host defense at the molecular level.
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