Proteolysis is a common microbial virulence mechanism that enables the destruction of host tissue and evasion from host defense mechanisms. Antimicrobial peptides, also known as host defense peptides, are effector molecules of the innate immunity that demonstrate a broad range of antimicrobial and immunoregulatory activities. Deficiency of the human LL-37 antimicrobial peptide was previously correlated with severe periodontal disease. Porphyromonas gingivalis, the major pathogen associated with periodontitis, is highly proteolytic. In this study, P. gingivalis was found capable of degrading LL-37 by utilizing its arginine-specific gingipains. Saliva collected from volunteers with a healthy periodontium protected LL-37 from proteolysis by P. gingivalis. Salivary protection of LL-37 was heat resistant and specific and enabled LL-37 to inhibit growth of Escherichia coli in the presence of the P. gingivalis proteases. Previously, saliva and other body fluids have been shown to inhibit the antimicrobial activity of LL-37. Here we demonstrate that at a cost of a small reduction in the bactericidal activity of LL-37, saliva enables the antibacterial activity of LL-37 despite the presence of proteases secreted by the main periodontopathogen.Cationic antimicrobial peptides are components of the innate immunity that mediate a broad range of antimicrobial activity and play an important role in mucosal protection (48). In mammals, antimicrobial peptides also function as immunomodulators of the innate immune system that alter gene expression in host cells, induce or modulate chemokine and cytokine production, and elicit or inhibit proinflammatory responses (6,24,40,46). Since the recognition of their immunoregulatory functions, antimicrobial peptides are often referred to as host defense peptides. The ␣-and ␤-defensins, histatins, and LL-37 antimicrobial peptides play an important role in protection of the oral cavity (7,11,20,36). LL-37, the only human host defense peptide of the cathelicidin family, is cleaved extracellularly from its 18-kDa human cationic antimicrobial protein (hCAP18) precursor into the biologically active 37-amino-acid antimicrobial peptide.Periodontitis is a chronic inflammatory disease that leads to destruction of the attachment apparatus of the teeth. Deficiency of salivary LL-37 in patients with morbus Kostmann syndrome (36) or with Papillon-Lefevre syndrome (10) was previously correlated with severe periodontitis. Porphyromonas gingivalis is an oral anaerobe and the pathogen most associated with chronic periodontal disease (16,18,42). P. gingivalis has previously been found to be highly resistant to antimicrobial peptides (1, 33). The Arg-gingipains and Lys-gingipain cysteine proteases (cleaving after arginine and lysine, respectively) are among the major virulence factors expressed and secreted by P. gingivalis. Being positively charged, arginine and lysine are highly represented in host defense peptides, including LL-37 (which has five arginines and six lysines). Not surprisingly, P. gingivalis w...