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

Abstract

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 <i>Leptospira</i>. In our comprehensive genomic analysis of 20 <i>Leptospira</i> spp. we identified seven pathogen-specific Two-Component System (TCS) proteins. Disruption of two these TCS genes in pathogenic <i>Leptospira</i> strain resulted in loss-of-virulence in a hamster model of leptospirosis. Corresponding genes <i>lvrA</i> and <i>lvrB (leptospira virulence regulator</i>) are juxtaposed in an operon and are predicted to encode a hybrid histidine kinase and a hybrid response regulator, respectively. Transcriptome analysis of <i>lvr</i> mutant strains with disruption of one (<i>lvrB</i>) or both genes (<i>lvrA/B</i>) 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 <i>lvrA</i> and <i>lvrB</i> evolved independently within different ecological lineages in <i>Leptospira</i> via gene duplication. This study uncovers a novel-signaling pathway that regulates virulence in pathogenic <i>Leptospira</i> (Lvr), providing a framework to understand the molecular bases of regulation in this life-threatening bacterium.