GILI BACHRACH'S LAB

Host defense peptides are innate immune effectors that possess both bactericidal activities and immunomodulatory functions. To our surprise, the level of LL-37, a host defense peptide thought to play a major role in defense against aggressive periodontitis, was normal in the saliva of individuals with Down's syndrome that suffer aggressive periodontitis. Our results led us to hypothesize that the bacteria involved in periodontitis in Down's syndrome are resistant to LL-37. Indeed, we found that Porphyromonas gingivalis, the pathogen associated with periodontitis in Down’s syndrome can hydrolyze LL-37 and that P. gingivalis also escapes LL-37 binding due to its unique envelope.

Studying proteolysis of LL-37 by periodontal pathogens under ex-vivo conditions in the presence of saliva, we found novel salivary mechanisms for protecting host immune effectors. We found saliva to irreversibly inhibit dentilisin, a major proteolytic virulence factor of Treponema denticola capable of hydrolyzing LL-37 and immunoglobulins (studied until then under in-vitro conditions lacking saliva).  

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Attempting to cleave LL-37 with different bacterial virulence-associated proteases in the presence of saliva, we also discovered that saliva contains factors, which we call protectorins. Protectorins bind and protect LL-37 from proteolysis, and enable its antimicrobial activity in the presence of the pathogens’ proteases. We demonstrated that actin and DNA act as salivary protectorins. Our results suggest that actin and DNA, presumably released by dead cells and abundant in infected sites, might be utilized by the immune system to enhance spatio-temporal immunity in an attempt to arrest infection and control inflammation.