Leptospira and Leptospirosis: New Systems Science Insights on Proteome,Posttranslational Modifications,and Pathogen-Host Interaction

Abstract

Leptospirosis is one of the most important zoonotic diseases for planetary health. It is caused by Leptospira spp., which poses a formidable challenge in both rural and urban geographies. Discovery of molecular targets is crucial for developing interventions, including vaccines, against leptospirosis. We report here novel systems science insights on Leptospira proteome, posttranslational modifications (PTMs), and pathogen-host interactions, with an eye to bacterial pathophysiology from a functional standpoint. A systematic reanalysis of unassigned spectra from our previous total proteome identification was used for a multi-PTM search. Notably, we identified 3693 unique high-confidence PTM sites corresponding to 1266 proteins (PTM-profiling probability cutoff value ≥75%). The majority of the phosphorylated peptides were found to be GroEL molecular chaperones. Notably, the molecular docking of PTM-GroEL with STAT3, an important signaling protein in cytokine production, resulted in the prediction of druggable “hotspots.” These energetically significant smaller subsets of amino acids (hotspot residues) offer promise for practical applications in planetary health, rational drug design, and peptide engineering. Furthermore, the prediction strategies described here could serve as a starting point for narrowing down the more extensive interface in protein-protein interactions that currently exist. Going forward, systems science approaches and the new insights reported here offer veritable prospects for innovation in preventing and treating leptospirosis.