Original Research ARTICLE
Lvr, A Signaling System That Controls Global Gene Regulation and Virulence In Pathogenic Leptospira
- 1Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, United States
- 2Laboratory of Molecular and Structural Biology, Institut Pasteur de Montevideo, Uruguay
- 3Yale Center for Genome Analysis, Yale University, United States
- 4Department of Biostatistics, Yale University, United States
- 5Oswaldo Cruz Foundation, Instituto Gonçalo Moniz (IGM), Brazil
- 6Lancaster University, United Kingdom
- 7Department of Microbiology, Monash Institute of Medical Research, Australia
- 8Center for Excellence in Structural and functional Microbial Genomics, Australian Research Council (ARC), Australia
- 9Department of Microbial Pathogenesis, Yale University, United States
- 10Biology of Spirochetes Unit, Institut Pasteur, 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.
Keywords: Leptospira, Pathogenic, branched signaling, two-component system, Virulence, evolution, hybrid histidine kinase, hybrid response regulator, Gene Duplication
Received: 28 Nov 2017;
Accepted: 08 Feb 2018.
Edited by:Kathleen McDonough, Wadsworth Center, United States
Reviewed by:Janakiram Seshu, University of Texas at San Antonio, United States
Ulisses P. Pereira, Universidade Estadual de Londrina, Brazil
Copyright: © 2018 Adhikarla, Wunder Jr, Mechaly, Mehta, Wang, Santos, Bisht, Diggle, Murray, Adler, Lopez-Giraldez, Townsend, Groisman, Picardeau, Buschiazzo and Ko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: PhD. Haritha Adhikarla, Yale School of Public Health, Yale University, Epidemiology of Microbial Diseases, LEPH 607, New Haven, 06510, CT, United States, email@example.com