Lvr, a signaling system that controls global gene regulation and virulence in pathogenic Leptospira

Haritha Adhikarla, Elsio A. Wunder, Ariel E. Mechaly, Sameet Mehta, Zheng Wang, Luciane Santos, Vimla Bisht, Peter Diggle, Gerald Murray, Ben Adler, Francesc Lopez, Jeffrey P. Townsend, Eduardo Groisman, Mathieu Picardeau, Alejandro Buschiazzo, Albert I. Ko

Research output: Contribution to journalArticleResearchpeer-review

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 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.

Original languageEnglish
Article number45
Number of pages13
JournalFrontiers in Cellular and Infection Microbiology
Volume8
DOIs
Publication statusPublished - 23 Feb 2018

Keywords

  • Branched signaling
  • Gene duplication
  • Hybrid histidine kinase
  • Hybrid response regulator
  • Leptospira
  • Pathogenic
  • Two-component system
  • Virulence

Cite this

Adhikarla, Haritha ; Wunder, Elsio A. ; Mechaly, Ariel E. ; Mehta, Sameet ; Wang, Zheng ; Santos, Luciane ; Bisht, Vimla ; Diggle, Peter ; Murray, Gerald ; Adler, Ben ; Lopez, Francesc ; Townsend, Jeffrey P. ; Groisman, Eduardo ; Picardeau, Mathieu ; Buschiazzo, Alejandro ; Ko, Albert I. / Lvr, a signaling system that controls global gene regulation and virulence in pathogenic Leptospira. In: Frontiers in Cellular and Infection Microbiology. 2018 ; Vol. 8.
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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 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.",
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author = "Haritha Adhikarla and Wunder, {Elsio A.} and Mechaly, {Ariel E.} and Sameet Mehta and Zheng Wang and Luciane Santos and Vimla Bisht and Peter Diggle and Gerald Murray and Ben Adler and Francesc Lopez and Townsend, {Jeffrey P.} and Eduardo Groisman and Mathieu Picardeau and Alejandro Buschiazzo and Ko, {Albert I.}",
year = "2018",
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doi = "10.3389/fcimb.2018.00045",
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Adhikarla, H, Wunder, EA, Mechaly, AE, Mehta, S, Wang, Z, Santos, L, Bisht, V, Diggle, P, Murray, G, Adler, B, Lopez, F, Townsend, JP, Groisman, E, Picardeau, M, Buschiazzo, A & Ko, AI 2018, 'Lvr, a signaling system that controls global gene regulation and virulence in pathogenic Leptospira' Frontiers in Cellular and Infection Microbiology, vol. 8, 45. https://doi.org/10.3389/fcimb.2018.00045

Lvr, a signaling system that controls global gene regulation and virulence in pathogenic Leptospira. / Adhikarla, Haritha; Wunder, Elsio A.; Mechaly, Ariel E.; Mehta, Sameet; Wang, Zheng; Santos, Luciane; Bisht, Vimla; Diggle, Peter; Murray, Gerald; Adler, Ben; Lopez, Francesc; Townsend, Jeffrey P.; Groisman, Eduardo; Picardeau, Mathieu; Buschiazzo, Alejandro; Ko, Albert I.

In: Frontiers in Cellular and Infection Microbiology, Vol. 8, 45, 23.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Adhikarla, Haritha

AU - Wunder, Elsio A.

AU - Mechaly, Ariel E.

AU - Mehta, Sameet

AU - Wang, Zheng

AU - Santos, Luciane

AU - Bisht, Vimla

AU - Diggle, Peter

AU - Murray, Gerald

AU - Adler, Ben

AU - Lopez, Francesc

AU - Townsend, Jeffrey P.

AU - Groisman, Eduardo

AU - Picardeau, Mathieu

AU - Buschiazzo, Alejandro

AU - Ko, Albert I.

PY - 2018/2/23

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N2 - 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.

AB - 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.

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KW - Hybrid response regulator

KW - Leptospira

KW - Pathogenic

KW - Two-component system

KW - Virulence

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