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PLoS Negl Trop Dis. 2016 Feb 18;10(2):e0004403. doi: 10.1371/journal.pntd.0004403. eCollection 2016 Feb.

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

Author information

1
J. Craig Venter Institute, Rockville, Maryland, United States of America.
2
Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
3
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
4
Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Clayton, Australia.
5
Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS, Salvador, Bahia, Brazil.
6
Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria, Australia.
7
Institut Pasteur de Montevideo, Laboratory of Molecular and Structural Microbiology, Montevideo, Uruguay.
8
Institut Pasteur, Department of Structural Biology and Chemistry, Paris, France.
9
Department of Population Medicine & Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
10
Centers for Disease Control and Prevention (DHHS, CDC, OID, NCEZID, DHCPP, BSPB), Atlanta, Georgia, United States of America.
11
VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
12
David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
13
WHO/FAO/OIE and National Collaborating Centre for Reference and Research on Leptospirosis, KIT Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, The Netherlands.
14
Government of Saskatchewan, Disease Control Laboratory Regina, Canada.
15
Department of Bioengineering, University of California, San Diego, La Jolla, California, United States of America.
16
Centro de Biotecnologia, Instituto Butantan, São Paulo, SP, Brazil.
17
Programa Interunidades em Biotecnologia, Instituto de Ciências Biomédicas, USP, São Paulo, SP, Brazil.
18
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
19
Institut Pasteur, Biology of Spirochetes Unit, National Reference Centre and WHO Collaborating Center for Leptospirosis, Paris, France.
20
Instituto de Medicina Tropical Alexander von Humboldt; Facultad de Medicina Alberto Hurtado, Universidd Peruana Cayetano Heredia, Lima, Peru.
21
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
22
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
23
Instituto de Medicina "Alexander von Humboldt," Universidad Peruana Cayetano Heredia, Lima, Peru.

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.

PMID:
26890609
PMCID:
PMC4758666
DOI:
10.1371/journal.pntd.0004403
[Indexed for MEDLINE]
Free PMC Article

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