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Front Cell Infect Microbiol. 2018 Feb 23;8:45. doi: 10.3389/fcimb.2018.00045. eCollection 2018.

Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira.

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Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United States.
Laboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Yale Centre for Genome Analysis, West Haven, CT, United States.
Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States.
Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Brazil.
Lancaster Medical School, Lancaster, United Kingdom.
Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC, Australia.
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, United States.
Institut Pasteur, "Biology of Spirochetes" Unit, Paris, France.
Department of Microbiology, Institut Pasteur, Paris, France.


Leptospirosis is an emerging zoonotic disease with more than 1 million cases annually. Currently there is lack of evidence for signaling pathways involved during the infection process of Leptospira. In our comprehensive genomic analysis of 20 Leptospira spp. we identified seven pathogen-specific Two-Component System (TCS) proteins. Disruption of two these TCS genes in pathogenic Leptospira strain resulted in loss-of-virulence in a hamster model of leptospirosis. Corresponding genes lvrA and lvrB (leptospira virulence regulator) are juxtaposed in an operon and are predicted to encode a hybrid histidine kinase and a hybrid response regulator, respectively. Transcriptome analysis of lvr mutant strains with disruption of one (lvrB) or both genes (lvrA/B) revealed global transcriptional regulation of 850 differentially expressed genes. Phosphotransfer assays demonstrated that LvrA phosphorylates LvrB and predicted further signaling downstream to one or more DNA-binding response regulators, suggesting that it is a branched pathway. Phylogenetic analyses indicated that lvrA and lvrB evolved independently within different ecological lineages in Leptospira via gene duplication. This study uncovers a novel-signaling pathway that regulates virulence in pathogenic Leptospira (Lvr), providing a framework to understand the molecular bases of regulation in this life-threatening bacterium.


Leptospira; branched signaling; gene duplication; hybrid histidine kinase; hybrid response regulator; pathogenic; two-component system; virulence

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