ROLE OF PROTEASES SECRETED BY LEPTOSPIRA IN THE DEGRADATION AND INACTIVATION OF HOST MOLECULES

Abstract

Leptospires are highly invasive spirochetes equipped with efficient strategies for dissemination in the host. Recently we demonstrated that pathogenic leptospires secrete proteases capable of cleaving and inactivating key molecules of the complement system, extracellular matrix and human plasma. In this project we intend to broaden the scope of investigation of possible targets of proteases secreted by pathogenic leptospires, as well as characterize a new metalloprotease, pappalysin, identified in previous proteomic studies performed by us.In subproject 1 recombinant pappalysin will be produced and its in vitro and in vivo effects will be evaluated on purified host molecules and on the microcirculation of the cremaster muscle of mice by intravital microscopy. In subproject 2 we aim to evaluate the role of proteases secreted by Leptospira in the degradation and inactivation of the antimicrobial peptide LL-37. Antimicrobial peptides are relatively resistant to proteolytic degradation, but there are reports of bacterial proteases with a broad spectrum of activity that efficiently cleave and inactivate such peptides.The characterization of mechanisms underlying the pathogenesis of leptospirosis has been our main line of research and we believe that this project may contribute to the future development of therapeutic and / or preventive strategies that may interfere in the process of invasion and tissue destruction observed in leptospirosis. (AU)