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A novel hybrid two-component system Lvr mediates virulence and global regulation in pathogenic Leptospira

ABSTRACT: Transmission of leptospirosis requires that the spirochete pathogen adapts rapidly to the mammalian host milieu during infection and the external environment upon shedding from the renal tubules of animal reservoirs. The pathogenic Leptospira genomes encode a notably large number (≥76) of putative two-component system (TCS) proteins, which presumably play a key role in switching the ecological niches. Yet to date, the regulatory networks that govern virulence and environmental adaptation have not been elucidated in Leptospira. We identified seven ORFs encoding putative TCS proteins that are exclusively conserved in all the pathogenic Leptospira species. Two of these ORFs (LMANv2_670020, LMANv2_670019), juxtaposed in an operon, are predicted to encode a cytoplasmic hybrid histidine kinase and response regulator. Corresponding transposon mutants ΔlvrA/B and ΔlvrB demonstrated a loss-of-virulence in a hamster model of leptospirosis and aberrant motility phenotype. RNA sequencing revealed the differential expression of transcripts on a global scale in ΔlvrA/B (8.13%), ΔlvrB (5.06%) and ΔlvrA/B∩ΔlvrB (8.24%). In vitro transcriptomes provided insights into the role of Lvr dyad in regulating virulence, motility, signal transduction and metabolism related genes. Phosphotransfer assays indicated that LvrA interacts with LvrB in a branched signaling pathway. Phylogenetic analyses indicated that Our findings suggest that a novel, hybrid two-component system Lvr plays a key role in governing virulence and mediating global regulation in pathogenic Leptospira.

ORGANISM(S): Leptospira interrogans serovar Manilae

PROVIDER: GSE79107 | GEO | 2018/04/04

REPOSITORIES: GEO

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Interplay between two peroxide stress regulators in the oxidative stress response and virulence of pathogenic Leptospira

Project description:Pathogenic Leptospira spp. are the causative agents of the zoonotic disease leptospirosis. During infection, Leptospira are confronted with deadly reactive oxygen species (ROS). Withstanding ROS produced by the host innate immunity is an important strategy evolved by pathogenic Leptospira for persisting in and colonizing hosts. The peroxide stress regulator, PerRA, represses genes involved in ROS defenses in L. interrogans. We have identified an ORF encoding a putative second PerR in pathogenic Leptospira that we named PerRB. We have determined the transcriptomic profil of a single perRB and a double perRAperRB mutants. The concomitant inactivation of perRA and perRB has a pleiotropic effect on the transcriptomic profil of L. interrogans. The lack of both PerRA and PerRB regulators led to the differential expression of several virulence-associated genes and a loss of virulence. Our findings provide new insights into a new regulatory network that controls virulence and host colonization.

2021-10-07 | GSE158051 | GEO

Analysis of the human endothelial cell response to pathogenic Leptospira interrogans vs. non-pathogenic Leptospira biflexa (HMEC data)

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Analysis of the human endothelial cell response to pathogenic Leptospira interrogans vs. non-pathogenic Leptospira biflexa (Eahy1 data)

2010-07-27 | GSE23172 | GEO

Adaptation of pathogenic Leptospira to oxidative stress

Project description:Pathogenic Leptospira spp. are the causative agents of the zoonotic disease leptospirosis. During infection, Leptospira are confronted with deadly reactive oxygen species (ROS). Withstanding ROS produced by the host innate immunity is an important strategy evolved by pathogenic Leptospira for persisting in and colonizing hosts. The peroxide stress regulator, PerR, represses genes involved in ROS defenses in L. interrogans. We have performed RNA sequencing in WT and perR mutant strains to characterize the L. interrogans adaptive response to hydrogen peroxide. We showed that Leptospira solicit three main peroxidase machineries (catalase, cytochrome C peroxidase and peroxiredoxin) and heme to adapt to peroxide stress as well as canonical chaperones of the heat shock response, and DNA repair. Determining the PerR regulon allowed to identify the PerR-dependent mechanisms of the peroxide adaptive response and has revealed a regulatory network involving other transcriptional regulators, two-component systems and sigma factors as well as non-coding RNAs that putatively orchestrate, in concert with PerR, this adaptive response. Our findings provide comprehensive insight into the mechanisms required by pathogenic Leptospira to overcome infection-related oxidants. This will participate in framing future hypothesis-driven studies to identify and decipher novel virulence mechanisms.

2020-09-22 | GSE140019 | GEO

Leptospira rLRR20 stimulates gene expressions in HK2 cell

Project description:Leptospires are highly motile bacteria that migrate from the breached skin to blood circulation of in human, allowing for their rapid dissemination and subsequent colonization of the liver, lungs, and kidneys. Pathogenic Leptospira contained numerous leucine-rich repeat (LRR) genes compared to non-pathogenic species that acted as virulence factors. The functions of the LRR proteins are still unknown and the relative responses of the host cell provided clear evidence that the regulation of host cell during Leptospirosis. We used microarrays to observation the global gene expression of human kidney epithelial cell (HK2 cell) under the treatment of rLRR20 protein.

2021-03-24 | GSE155061 | GEO

RNA sequencing to profile transcriptomes in murine bone-marrow-derived macrophages upon infection with Leptospira spp.

Project description:Leptospirosis is a re-emerging zoonosis, a globally important infectious disease, caused by an infection with the genus Leptospira. Leptospirosis is associated with acute kidney injury and progress to CKD due to sustained tubulointerstitial inflammation. Macrophages play a critical role in controlling the bacterial burden and tissue inflammation during the spirochete infections. To understand the molecular mechanisms of leptospia-induced macrophage activation and its role in the inflammatory process, we performed the transcriptome profiles of murine bone marrow-derived macrophages infected with pathogenic and non-pathogenuc Leptospira spp.at a multiplicity of infection of 100 for 2 and 24 hrs, respectively.

2022-05-11 | GSE166050 | GEO

Analysis of the human endothelial cell response to pathogenic Leptospira interrogans vs. non-pathogenic Leptospira biflexa (HMEC data)

Project description:The overall goal of these experiments was to determine how human endothelial cells respond to pathogenic Leptospira interrogans. Leptospira interrogans causes leptospirosis, the most widespread zoonotic infection in the world. A hallmark of leptospirosis is widespread endothelial damage, which in severe cases leads to hemorrhage. In these experiments, we infected two endothelial cell lines with pathogenic Leptospira interrogans serovar Canicola strain Ca12-005, and as controls, with the non-pathogenic Leptospira biflexa serovar Patoc strain Pfra. As additional controls, uninfected cells were also included in the analyses. The cell line used fhere was a microvascular endothelial line, HMEC (Ades et al, 1992. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol. 99:683-690); due to loss of the original analysis files, only raw data files are provided. Infection times were performed at a multiplicity of infection (# bacteria/endothelial cell) of 10 for either 1 hour or 3 hours, after which RNA was harvested and reverse transcribed. Labeled cDNAs were used to probe HEEBO arrays purchased from Microarrays Inc. (Nashville, TN). In each of three biological replicate experiments, for each time point, three comparisons were made. First, the L. interrogans-infected cells were compared to the L. biflexa-infected cells. Second, the L. Interrogans-infected cells were compared to the uninfected cells. Third, the L. biflexa-infected cells were compared to the uninfected cells. A second endothelial cell line,

2010-07-27 | E-GEOD-23173 | biostudies-arrayexpress

Analysis of the human endothelial cell response to pathogenic Leptospira interrogans vs. non-pathogenic Leptospira biflexa (Eahy1 data)

Project description:The overall goal of these experiments was to determine how human endothelial cells respond to pathogenic Leptospira interrogans. Leptospira interrogans causes leptospirosis, the most widespread zoonotic infection in the world. A hallmark of leptospirosis is widespread endothelial damage, which in severe cases leads to hemorrhage. In these experiments, we infected two endothelial cell lines with pathogenic Leptospira interrogans serovar Canicola strain Ca12-005, and as controls, with the non-pathogenic Leptospira biflexa serovar Patoc strain Pfra. As additional controls, uninfected cells were also included in the analyses. The cell line used was Ea.hy926, a macrovascular line (Edgell, C. J.,et al. 1990. In vitro Cell. & Dev. Biol. 26:1167-1172, and Edgell, C. J., et al. 1983. Proc. Natl. Acad. Sci. 80:3734-3737). Infection times were performed at a multiplicity of infection (# bacteria/endothelial cell) of 10 for either 1 hour or 3 hours, after which RNA was harvested and reverse transcribed. Labeled cDNAs were used to probe HEEBO arrays purchased from Microarrays Inc. (Nashville, TN). In each of three biological replicate experiments, for each time point, three comparisons were made. First, the L. interrogans-infected cells were compared to the L. biflexa-infected cells. Second, the L. Interrogans-infected cells were compared to the uninfected cells. Third, the L. biflexa-infected cells were compared to the uninfected cells. A second endothelial cell line, HMEC (Ades et al, 1992. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol. 99:683-690), which is of microvascular origin, was also used; raw data files are provided separately.

2010-07-27 | E-GEOD-23172 | biostudies-arrayexpress

RNAseq of kidneys from a mice model of chronic leptospirosis infection and induced a secondary nephrotoxic injury by adenine feeding

Project description:Background The mysterious chronic kidney disease is multifactorial causes. One of the risk factors is leptospirosis, a re-emerging infectious disease caused by Leptospira spp., for endemic leptospirosis tend to coincide with high-incidence regions of chronic kidney disease of unknown etiology. This study aims to investigate the role of leptospirosis as an emerging culprit in which chronic subclinical kidney injury, may predispose to progressive kidney disease when superimposed on secondary nephrotoxic injury. Methods Adenine-induced renal injury in chronic leptospira-infected C57/BL6 mice were studied for evaluating the renal function, histology and gene expression changes. We employed RNA sequencing-based renal transcriptome to investigate pathogenic pathways associated with secondary nephrotoxic injury in chronic kidney injury due to leptospirosis. Results The severity of kidney lesions was increased and the expression of immune/inflammation/fibrosis genes were significantly up-regulated in either low-dose (0.1%) and high-dose (0.2%) adenine-induced renal injury superimposed on infected mice. Whole renal transcriptome analysis reveals that the substantial amplification of the tremendous amount of expressed genes and fibrosis-related pathways was found in adenine-induced kidney injury add-on to leptospira-infected mice which correlated with kidney dysfunction and fibrosis compared to infection or adenine itself. A total of 41 differentially expressed genes associated with fibrosis were identified in infected mice fed with adenine, suggesting that these potential genes contributed to aggravated renal progression occurred in adenine-fed chronic leptospira-infected mice. Conclusions In summary, this study indicates that chronic subclinical kidney infection when exposed to different degree of secondary nephrotoxic injury may predispose to exacerbated and progressive chronic kidney disease.

2021-04-05 | GSE150641 | GEO

Transcriptome analysis of murine macrophages infected with different strains of Leptospira spp

Project description:Leptospirosis is a neglected zoonotic disease of global importance. Despite its prevalence, pathogenesis is still poorly understood. Our aim was to discover transcripts responsable for pathogenicity of leptospirosis. We compared the transcriptome profiles of saprophyte, attenuated and virulent strain of Leptospira spp.

2018-02-13 | GSE105141 | GEO

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