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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.

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