What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira

Leptospirosis,caused by spirochetes of the genus leptospira,is a globally widespread,neglected and emerging zoonotic disease. while whole genome analysis of individual pathogenic,intermediately pathogenic and saprophytic leptospira species has been reported,comprehensive cross-species genomic comparison of all known species of infectious and non-infectious leptospira,with the goal of identifying genes related to pathogenesis and mammalian host adaptation,remains a key gap in the field. infectious leptospira,comprised of pathogenic and intermediately pathogenic leptospira,evolutionarily diverged from non-infectious,saprophytic leptospira,as demonstrated by the following computational biology analyses: 1) the definitive taxonomy and evolutionary relatedness among all known leptospira species; 2) genomically-predicted metabolic reconstructions that indicate novel adaptation of infectious leptospira to mammals,including sialic acid biosynthesis,pathogen-specific porphyrin metabolism and the first-time demonstration of cobalamin (b12) autotrophy as a bacterial virulence factor; 3) crispr/cas systems demonstrated only to be present in pathogenic leptospira,suggesting a potential mechanism for this clade’s refractoriness to gene targeting; 4) finding leptospira pathogen-specific specialized protein secretion systems; 5) novel virulence-related genes/gene families such as the virulence modifying (vm) (pf07598 paralogs) proteins and pathogen-specific adhesins; 6) discovery of novel,pathogen-specific protein modification and secretion mechanisms including unique lipoprotein signal peptide motifs,sec-independent twin arginine protein secretion motifs,and the absence of certain canonical signal recognition particle proteins from all leptospira; and 7) and demonstration of infectious leptospira-specific signal-responsive gene expression,motility and chemotaxis systems. by identifying large scale changes in infectious (pathogenic and intermediately pathogenic) vs. non-infectious leptospira,this work provides new insights into the evolution of a genus of bacterial pathogens. this work will be a comprehensive roadmap for understanding leptospirosis pathogenesis. more generally,it provides new insights into mechanisms by which bacterial pathogens adapt to mammalian hosts. © 2016 almeida et al.