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Genomic insights into the pathogenesis of Leptospira


Leptospirosis is a zoonosis worldwide distribution, difficult diagnosis and underestimated burden. Most of its virulence factors remain unknown. The identification and characterization of a novel species of intermediate Leptospira isolated from humans and rodents from the Peruvian Amazon are described in this dissertation. This new specie has been denominated L. licerasiae. The genome of this new species was sequenced and analyzed. It has characteristics that are closer to those of pathogens than to those of saprophytic leptospires. This new genome was compared with other known leptospiral genomes to predict virulence factor by identifying genes unique to pathogenic leptospires. Enzymes required for the synthesis of sialic acid were found among the genes unique to pathogens. Various pathogenic bacteria use sialic acids as a mechanism for immune evasion by promoting complement factor H binding and therefore preventing activation of the alternative pathway response. A biochemical approach was used to demonstrate the synthesis of sialic acids by pathogenic leptospires. Potential localizations for sialic acid identified by MS/peptide identification and HPLC include the virulence factor Loa22, the lipoprotein LipL32 and lipopolsaccharide. The sequences of known leptospiral lipoproteins were identified in L. licerasiae and compared with the sequences of lipoproteins from pathogenic leptospires. Differences were found in the sequence of the signal peptide, particularly in the lipobox region that determines cleavage by signal peptidases, membrane export and lipidation. It was found that the virulence factor Loa22, among other lipoproteins in L. licerasiae, has lost the characteristics necessary for a functional lipobox. Palmitate labeling shows differences in the pattern of protein lipidation between L. licerasiae and the pathogen L. interrogans. Live immunofluorescence studies show that Loa 2 is not expressed in the surface of L. licerasiae or expressed in much lower levels than in the pathogen L. interrogans, while LipL71 and LipL32 continue to be detected in the surface. Loss of the lipobox and therefore loss of membranelocalization and post-translational modifications including sialylation could be mechanisms responsible for the less significant virulence of L. licerasiae.

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