Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fcimb.2018.00045/full |
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| author | Haritha Adhikarla Elsio A. Wunder Ariel E. Mechaly Sameet Mehta Zheng Wang Luciane Santos Luciane Santos Vimla Bisht Peter Diggle Gerald Murray Ben Adler Ben Adler Francesc Lopez Jeffrey P. Townsend Eduardo Groisman Mathieu Picardeau Alejandro Buschiazzo Alejandro Buschiazzo Albert I. Ko Albert I. Ko |
| author_facet | Haritha Adhikarla Elsio A. Wunder Ariel E. Mechaly Sameet Mehta Zheng Wang Luciane Santos Luciane Santos Vimla Bisht Peter Diggle Gerald Murray Ben Adler Ben Adler Francesc Lopez Jeffrey P. Townsend Eduardo Groisman Mathieu Picardeau Alejandro Buschiazzo Alejandro Buschiazzo Albert I. Ko Albert I. Ko |
| author_sort | Haritha Adhikarla |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T13:12:11Z |
| format | Article |
| id | doaj.art-afcbd147e40b45dca97d44cad4635187 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-12T13:12:11Z |
| publishDate | 2018-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-afcbd147e40b45dca97d44cad46351872022-12-22T03:31:51ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-02-01810.3389/fcimb.2018.00045335134Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic LeptospiraHaritha Adhikarla0Elsio A. Wunder1Ariel E. Mechaly2Sameet Mehta3Zheng Wang4Luciane Santos5Luciane Santos6Vimla Bisht7Peter Diggle8Gerald Murray9Ben Adler10Ben Adler11Francesc Lopez12Jeffrey P. Townsend13Eduardo Groisman14Mathieu Picardeau15Alejandro Buschiazzo16Alejandro Buschiazzo17Albert I. Ko18Albert I. Ko19Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United StatesDepartment of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United StatesLaboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, UruguayYale Centre for Genome Analysis, West Haven, CT, United StatesDepartment of Biostatistics, Yale School of Public Health, New Haven, CT, United StatesDepartment of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United StatesGonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, BrazilDepartment of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United StatesLancaster Medical School, Lancaster, United KingdomDepartment of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaAustralian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC, AustraliaYale Centre for Genome Analysis, West Haven, CT, United StatesDepartment of Biostatistics, Yale School of Public Health, New Haven, CT, United StatesDepartment of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, United States0Institut Pasteur, “Biology of Spirochetes” Unit, Paris, FranceLaboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay1Department of Microbiology, Institut Pasteur, Paris, FranceDepartment of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, United StatesGonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, BrazilLeptospirosis 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.http://journal.frontiersin.org/article/10.3389/fcimb.2018.00045/fullLeptospirapathogenicbranched signalingtwo-component systemhybrid histidine kinasehybrid response regulator |
| spellingShingle | Haritha Adhikarla Elsio A. Wunder Ariel E. Mechaly Sameet Mehta Zheng Wang Luciane Santos Luciane Santos Vimla Bisht Peter Diggle Gerald Murray Ben Adler Ben Adler Francesc Lopez Jeffrey P. Townsend Eduardo Groisman Mathieu Picardeau Alejandro Buschiazzo Alejandro Buschiazzo Albert I. Ko Albert I. Ko Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira Frontiers in Cellular and Infection Microbiology Leptospira pathogenic branched signaling two-component system hybrid histidine kinase hybrid response regulator |
| title | Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira |
| title_full | Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira |
| title_fullStr | Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira |
| title_full_unstemmed | Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira |
| title_short | Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira |
| title_sort | lvr a signaling system that controls global gene regulation and virulence in pathogenic leptospira |
| topic | Leptospira pathogenic branched signaling two-component system hybrid histidine kinase hybrid response regulator |
| url | http://journal.frontiersin.org/article/10.3389/fcimb.2018.00045/full |
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