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

Haritha Adhikarla (1) , Elsio A. Jr Wunder (1) , Ariel E Mechaly (2) , Sameet Mehta (3) , Zheng Wang (1) , Luciane Santos (1, 4) , Vimla Bisht (1) , Peter Diggle (5) , Gerald Murray (6) , Ben Adler (6) , Francesc Lopez (3) , Jeffrey P Townsend (1) , Eduardo Groisman (7) , Mathieu Picardeau (8) , Alejandro Buschiazzo (2, 9) , Albert I Ko (1, 4)

1 YSPH - Yale School of Public Health
2 Institut Pasteur de Montevideo
3 YCGA - Yale Centre for Genome Analysis
4 FIOCRUZ - Fundação Oswaldo Cruz / Oswaldo Cruz Foundation
5 Lancaster University
6 Monash University [Clayton]
7 YSM - Yale School of Medicine [New Haven, Connecticut]
8 Biologie des Spirochètes / Biology of Spirochetes
9 Département de Microbiologie - Department of Microbiology

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.

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

Domaines: Sciences du Vivant [q-bio]; Microbiologie et Parasitologie; Bactériologie

Haritha Adhikarla, Elsio A. Jr Wunder, Ariel E Mechaly, Sameet Mehta, Zheng Wang, et al.. Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira. Frontiers in Cellular and Infection Microbiology, 2018, 8, pp.45. ⟨10.3389/fcimb.2018.00045⟩. ⟨pasteur-02100138⟩