title: What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira.
abstract: 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.
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Derrick E
authors.initials: DE
authors.lastname: Fouts
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthias
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Haritha
authors.initials: H
authors.lastname: Adhikarla
authors.affiliation: Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Clayton, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Adler
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS, Salvador, Bahia, Brazil.
authors.forename: Luciane
authors.initials: L
authors.lastname: Amorim-Santos
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Berg
authors.affiliation: Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria, Australia.
authors.forename: Dieter
authors.initials: D
authors.lastname: Bulach
authors.affiliation: Institut Pasteur de Montevideo, Laboratory of Molecular and Structural Microbiology, Montevideo, Uruguay.|Institut Pasteur, Department of Structural Biology and Chemistry, Paris, France.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Buschiazzo
authors.affiliation: Department of Population Medicine & Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: Yung-Fu
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Centers for Disease Control and Prevention (DHHS, CDC, OID, NCEZID, DHCPP, BSPB), Atlanta, Georgia, United States of America.
authors.forename: Renee L
authors.initials: RL
authors.lastname: Galloway
authors.affiliation: VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.|David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Haake
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Haft
authors.affiliation: WHO/FAO/OIE and National Collaborating Centre for Reference and Research on Leptospirosis, KIT Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, The Netherlands.
authors.forename: Rudy
authors.initials: R
authors.lastname: Hartskeerl
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS, Salvador, Bahia, Brazil.
authors.forename: Albert I
authors.initials: AI
authors.lastname: Ko
authors.affiliation: Government of Saskatchewan, Disease Control Laboratory Regina, Canada.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Levett
authors.affiliation: VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.|David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Matsunaga
authors.affiliation: Institut Pasteur de Montevideo, Laboratory of Molecular and Structural Microbiology, Montevideo, Uruguay.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Mechaly
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Monk
authors.affiliation: Centro de Biotecnologia, Instituto Butantan, São Paulo, SP, Brazil.|Programa Interunidades em Biotecnologia, Instituto de Ciências Biomédicas, USP, São Paulo, SP, Brazil.
authors.forename: Ana L T
authors.initials: AL
authors.lastname: Nascimento
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, United States of America.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Nelson
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Palsson
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.affiliation: Institut Pasteur, Biology of Spirochetes Unit, National Reference Centre and WHO Collaborating Center for Leptospirosis, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Picardeau
authors.affiliation: Instituto de Medicina Tropical Alexander von Humboldt; Facultad de Medicina Alberto Hurtado, Universidd Peruana Cayetano Heredia, Lima, Peru.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Ricaldi
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Janjira
authors.initials: J
authors.lastname: Thaipandungpanit
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.|Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS, Salvador, Bahia, Brazil.
authors.forename: Elsio A
authors.initials: EA
authors.lastname: Wunder
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: X Frank
authors.initials: XF
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.|Instituto de Medicina Tropical Alexander von Humboldt; Facultad de Medicina Alberto Hurtado, Universidd Peruana Cayetano Heredia, Lima, Peru.|Instituto de Medicina "Alexander von Humboldt," Universidad Peruana Cayetano Heredia, Lima, Peru.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vinetz
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D058947:Bacterial Secretion Systems; D001483:Base Sequence; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D023281:Genomics; D006801:Humans; D007919:Leptospira / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D007922:Leptospirosis / Q000382:microbiology* / Q000662:veterinary*; D008969:Molecular Sequence Data; D010802:Phylogeny; D021382:Protein Sorting Signals; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D021382:Protein Sorting Signals