scholarly journals The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila

2015 ◽  
Vol 197 (18) ◽  
pp. 3015-3025 ◽  
Author(s):  
Elizabeth A. Hussa ◽  
Ángel M. Casanova-Torres ◽  
Heidi Goodrich-Blair
Keyword(s):  
Transcription Factor ◽  
Phenotypic Variation ◽  
Pathogenic Bacteria ◽  
Regulatory Protein ◽  
Inverse Correlation ◽  
Xenorhabdus Nematophila ◽  
Insect Larvae ◽  
Content Type ◽  
Expression Levels

ABSTRACTThe bacteriumXenorhabdus nematophilaengages in phenotypic variation with respect to pathogenicity against insect larvae, yielding both virulent and attenuated subpopulations of cells from an isogenic culture. The global regulatory protein Lrp is necessary forX. nematophilavirulence and immunosuppression in insects, as well as colonization of the mutualistic host nematodeSteinernema carpocapsae, and mediates expression of numerous genes implicated in each of these phenotypes. Given the central role of Lrp inX. nematophilahost associations, as well as its involvement in regulating phenotypic variation pathways in other bacteria, we assessed its function in virulence modulation. We discovered that expression oflrpvaries within an isogenic population, in a manner that correlates with modulation of virulence. Unexpectedly, although Lrp is necessary for optimal virulence and immunosuppression, cells expressing high levels oflrpwere attenuated in these processes relative to those with low to intermediatelrpexpression. Furthermore, fixed expression oflrpat high and low levels resulted in attenuated and normal virulence and immunosuppression, respectively, and eliminated population variability of these phenotypes. These data suggest that fluctuatinglrpexpression levels are sufficient to drive phenotypic variation inX. nematophila.IMPORTANCEMany bacteria use cell-to-cell phenotypic variation, characterized by distinct phenotypic subpopulations within an isogenic population, to cope with environmental change. Pathogenic bacteria utilize this strategy to vary antigen or virulence factor expression. Our work establishes that the global transcription factor Lrp regulates phenotypic variation in the insect pathogenXenorhabdus nematophila, leading to attenuation of virulence and immunosuppression in insect hosts. Unexpectedly, we found an inverse correlation between Lrp expression levels and virulence: high levels of expression of Lrp-dependent putative virulence genes are detrimental for virulence but may have an adaptive advantage in other aspects of the life cycle. Investigation ofX. nematophilaphenotypic variation facilitates dissection of this phenomenon in the context of a naturally occurring symbiosis.

scholarly journals hfqPlays Important Roles in Virulence and Stress Adaptation in Cronobacter sakazakii ATCC 29544

2015 ◽  
Vol 83 (5) ◽  
pp. 2089-2098 ◽  
Author(s):  
Seongok Kim ◽  
Hyelyeon Hwang ◽  
Kwang-Pyo Kim ◽  
Hyunjin Yoon ◽  
Dong-Hyun Kang ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
Soft Agar ◽  
Host Cells ◽  
Neonatal Meningitis ◽  
Animal Cells ◽  
Content Type ◽  
Flagellar Biosynthesis

Cronobacterspp. are opportunistic pathogens that cause neonatal meningitis and sepsis with high mortality in neonates. Despite the peril associated withCronobacterinfection, the mechanisms of pathogenesis are still being unraveled. Hfq, which is known as an RNA chaperone, participates in the interaction with bacterial small RNAs (sRNAs) to regulate posttranscriptionally the expression of various genes. Recent studies have demonstrated that Hfq contributes to the pathogenesis of numerous species of bacteria, and its roles are varied between bacterial species. Here, we tried to elucidate the role of Hfq inC. sakazakiivirulence. In the absence ofhfq,C. sakazakiiwas highly attenuated in disseminationin vivo, showed defects in invasion (3-fold) into animal cells and survival (103-fold) within host cells, and exhibited low resistance to hydrogen peroxide (102-fold). Remarkably, the loss ofhfqled to hypermotility on soft agar, which is contrary to what has been observed in other pathogenic bacteria. The hyperflagellated bacteria were likely to be attributable to the increased transcription of genes associated with flagellar biosynthesis in a strain lackinghfq. Together, these data strongly suggest thathfqplays important roles in the virulence ofC. sakazakiiby participating in the regulation of multiple genes.

scholarly journals Comparative Transcriptomics Highlights the Role of the Activator Protein 1 Transcription Factor in the Host Response to Ebolavirus

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
James W. Wynne ◽  
Shawn Todd ◽  
Victoria Boyd ◽  
Mary Tachedjian ◽  
Reuben Klein ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Lines ◽  
Human Cells ◽  
Activator Protein 1 ◽  
Host Gene Expression ◽  
Rna Seq ◽  
Content Type ◽  
Molecular Events ◽  
Ebov Infection

ABSTRACT Ebolavirus and Marburgvirus comprise two genera of negative-sense single-stranded RNA viruses that cause severe hemorrhagic fevers in humans. Despite considerable research efforts, the molecular events following Ebola virus (EBOV) infection are poorly understood. With the view of identifying host factors that underpin EBOV pathogenesis, we compared the transcriptomes of EBOV-infected human, pig, and bat kidney cells using a transcriptome sequencing (RNA-seq) approach. Despite a significant difference in viral transcription/replication between the cell lines, all cells responded to EBOV infection through a robust induction of extracellular growth factors. Furthermore, a significant upregulation of activator protein 1 (AP1) transcription factor complex members FOS and JUN was observed in permissive cell lines. Functional studies focusing on human cells showed that EBOV infection induces protein expression, phosphorylation, and nuclear accumulation of JUN and, to a lesser degree, FOS. Using a luciferase-based reporter, we show that EBOV infection induces AP1 transactivation activity within human cells at 48 and 72 h postinfection. Finally, we show that JUN knockdown decreases the expression of EBOV-induced host gene expression. Taken together, our study highlights the role of AP1 in promoting the host gene expression profile that defines EBOV pathogenesis. IMPORTANCE Many questions remain about the molecular events that underpin filovirus pathophysiology. The rational design of new intervention strategies, such as postexposure therapeutics, will be significantly enhanced through an in-depth understanding of these molecular events. We believe that new insights into the molecular pathogenesis of EBOV may be possible by examining the transcriptomic response of taxonomically diverse cell lines (derived from human, pig, and bat). We first identified the responsive pathways using an RNA-seq-based transcriptomics approach. Further functional and computational analysis focusing on human cells highlighted an important role for the AP1 transcription factor in mediating the transcriptional response to EBOV infection. Our study sheds new light on how host transcription factors respond to and promote the transcriptional landscape that follows viral infection.

scholarly journals The β-Arrestin-Like Protein Rim8 Is Hyperphosphorylated and Complexes with Rim21 and Rim101 To Promote Adaptation to Neutral-Alkaline pH

2012 ◽  
Vol 11 (5) ◽  
pp. 683-693 ◽  
Author(s):  
Jonathan Gomez-Raja ◽  
Dana A. Davis
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
G Protein ◽  
Signal Transduction Pathway ◽  
Multivesicular Bodies ◽  
Ph Sensing ◽  
Content Type ◽  
Protein Levels ◽  
G Protein Coupled

ABSTRACTβ-Arrestin proteins are critical for G-protein-coupled receptor desensitization and turnover. However, β-arrestins have recently been shown to play direct roles in nonheterotrimeric G-protein signal transduction. TheCandida albicansβ-arrestin-like protein Rim8 is required for activation of the Rim101 pH-sensing pathway and for pathogenesis. We have found thatC. albicansRim8 is posttranslationally modified by phosphorylation and specific phosphorylation states are associated with activation of the pH-sensing pathway. Rim8 associated with both the receptor Rim21 and the transcription factor Rim101, suggesting that Rim8 bridges the signaling and activation steps of the pathway. Finally, upon activation of the Rim101 transcription factor,C. albicansRim8 was transcriptionally repressed and Rim8 protein levels were rapidly reduced. Our studies suggest that Rim8 is taken up into multivesicular bodies and degraded within the vacuole. In total, our results reveal a novel mechanism for tightly regulating the activity of a signal transduction pathway. Although the role of β-arrestin proteins in mammalian signal transduction pathways has been demonstrated, relatively little is known about how β-arrestins contribute to signal transduction. Our analyses provide some insights into potential roles.

scholarly journals Novel Mutations Associated with Clofazimine Resistance inMycobacterium abscessus

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Yuanyuan Chen ◽  
Jiazhen Chen ◽  
Shuo Zhang ◽  
Wanliang Shi ◽  
Wenhong Zhang ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Regulatory Protein ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Mechanisms Of Resistance ◽  
Novel Mutations ◽  
Content Type ◽  
Future Studies ◽  
Transcriptional Regulatory

ABSTRACTMycobacterium abscessusis a major nontuberculous mycobacterial (NTM) pathogen and is responsible for about 80% of all pulmonary infections caused by rapidly growing mycobacteria. Clofazimine is an effective drug active againstM. abscessus, but the mechanism of resistance to clofazimine inM. abscessusis unknown. To investigate the molecular basis of clofazimine resistance inM. abscessus, we isolated 29M. abscessusmutants resistant to clofazimine and subjected them to whole-genome sequencing to identify possible mutations associated with clofazimine resistance. We found that mutations in the MAB_2299c gene (which encodes a possible transcriptional regulatory protein), MAB_1483, and MAB_0540 are most commonly associated with clofazimine resistance. In addition, mutations in MAB_0416c, MAB_4099c, MAB_2613, MAB_0409, and MAB_1426 were also associated with clofazimine resistance but less frequently. Two identical mutations which are likely to be polymorphisms unrelated to clofazimine resistance were found in MAB_4605c and MAB_4323 in 13 mutants. We conclude that mutations in MAB_2299c, MAB_1483, and MAB_0540 are the major mechanisms of clofazimine resistance inM. abscessus. Future studies are needed to address the role of the identified mutations in clofazimine resistance inM. abscessus. Our findings have implications for understanding mechanisms of resistance to clofazimine and for rapid detection of clofazimine resistance in this organism.

scholarly journals ThechbGGene of the Chitobiose (chb) Operon of Escherichia coli Encodes a Chitooligosaccharide Deacetylase

2012 ◽  
Vol 194 (18) ◽  
pp. 4959-4971 ◽  
Author(s):  
Subhash Chandra Verma ◽  
Subramony Mahadevan
Keyword(s):  
Escherichia Coli ◽  
Metal Binding ◽  
Inflammatory Diseases ◽  
Regulatory Protein ◽  
Loss Of Function ◽  
Content Type ◽  
Reading Frame ◽  
E Coli ◽  
Evolutionarily Conserved

ABSTRACTThechboperon ofEscherichia coliis involved in the utilization of the β-glucosides chitobiose and cellobiose. The function ofchbG(ydjC), the sixth open reading frame of the operon that codes for an evolutionarily conserved protein is unknown. We show thatchbGencodes a monodeacetylase that is essential for growth on the acetylated chitooligosaccharides chitobiose and chitotriose but is dispensable for growth on cellobiose and chitosan dimer, the deacetylated form of chitobiose. The predicted active site of the enzyme was validated by demonstrating loss of function upon substitution of its putative metal-binding residues that are conserved across the YdjC family of proteins. We show that activation of thechbpromoter by the regulatory protein ChbR is dependent on ChbG, suggesting that deacetylation of chitobiose-6-P and chitotriose-6-P is necessary for their recognition by ChbR as inducers. Strains carrying mutations inchbRconferring the ability to grow on both cellobiose and chitobiose are independent ofchbGfunction for induction, suggesting that gain of function mutations in ChbR allow it to recognize the acetylated form of the oligosaccharides. ChbR-independent expression of the permease and phospho-β-glucosidase from a heterologous promoter did not support growth on both chitobiose and chitotriose in the absence ofchbG, suggesting an additional role ofchbGin the hydrolysis of chitooligosaccharides. The homologs ofchbGin metazoans have been implicated in development and inflammatory diseases of the intestine, indicating that understanding the function ofE. colichbGhas a broader significance.

scholarly journals Evolutionary Adaptation of an AraC-Like Regulatory Protein in Citrobacter rodentium and Escherichia Species

2015 ◽  
Vol 83 (4) ◽  
pp. 1384-1395 ◽  
Author(s):  
Aimee Tan ◽  
Nicola K. Petty ◽  
Dianna Hocking ◽  
Vicki Bennett-Wood ◽  
Matthew Wakefield ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Regulatory Protein ◽  
Gene Repertoire ◽  
Citrobacter Rodentium ◽  
Environmental Strain ◽  
Content Type ◽  
E Coli ◽  
Genes Encoding

The evolution of pathogenic bacteria is a multifaceted and complex process, which is strongly influenced by the horizontal acquisition of genetic elements and their subsequent expression in their new hosts. A well-studied example is the RegA regulon of the enteric pathogenCitrobacter rodentium. The RegA regulatory protein is a member of the AraC/XylS superfamily, which coordinates the expression of a gene repertoire that is necessary for full pathogenicity of this murine pathogen. Upon stimulation by an exogenous, gut-associated signal, namely, bicarbonate ions, RegA activates the expression of a series of genes, including virulence factors, such as autotransporters, fimbriae, a dispersin-like protein, and thegrlRAoperon on the locus of enterocyte effacement pathogenicity island. Interestingly, the genes encoding RegA homologues are distributed across the genusEscherichia, encompassing pathogenic and nonpathogenic subtypes. In this study, we carried out a series of bioinformatic, transcriptional, and functional analyses of the RegA regulons of these bacteria. Our results demonstrated thatregAhas been horizontally transferred toEscherichiaspp. andC. rodentium. Comparative studies of two RegA homologues, namely, those fromC. rodentiumandE. coliSMS-3-5, a multiresistant environmental strain ofE. coli, showed that the two regulators acted similarlyin vitrobut differed in terms of their abilities to activate the virulence ofC. rodentiumin vivo, which evidently was due to their differential activation ofgrlRA. Our data indicate that RegA fromC. rodentiumhas strain-specific adaptations that facilitate infection of its murine host. These findings shed new light on the development of virulence byC. rodentiumand on the evolution of virulence-regulatory genes of bacterial pathogens in general.

scholarly journals The Enigmatic Genome of an Obligate Ancient Spiroplasma Symbiont in a Hadal Holothurian

2017 ◽  
Vol 84 (1) ◽  
Author(s):  
Li-Sheng He ◽  
Pei-Wei Zhang ◽  
Jiao-Mei Huang ◽  
Fang-Chao Zhu ◽  
Antoine Danchin ◽  
...  
Keyword(s):  
Sea Cucumber ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Mariana Trench ◽  
Sea Cucumbers ◽  
Content Type ◽  
Sugar Transporters ◽  
Basal Group ◽  
Microbial Toxin

ABSTRACTProtective symbiosis has been reported in many organisms, but the molecular mechanisms of the mutualistic interactions between the symbionts and their hosts are unclear. Here, we sequenced the 424-kbp genome of “CandidatusSpiroplasma holothuricola,” which dominated the hindgut microbiome of a sea cucumber, a major scavenger captured in the Mariana Trench (6,140 m depth). Phylogenetic relationships indicated that the dominant bacterium in the hindgut was derived from a basal group ofSpiroplasmaspecies. In this organism, the genes responsible for the biosynthesis of amino acids, glycolysis, and sugar transporters were lost, strongly suggesting endosymbiosis. The highly decayed genome consists of two chromosomes and harbors genes coding for proteolysis, microbial toxin, restriction-methylation systems, and clustered regularly interspaced short palindromic repeats (CRISPRs), composed of threecasgenes and 76 CRISPR spacers. The holothurian host is probably protected against invading viruses from sediments by the CRISPRs/Cas and restriction systems of the endosymbiotic spiroplasma. The protective endosymbiosis indicates the important ecological role of the ancientSpiroplasmasymbiont in the maintenance of hadal ecosystems.IMPORTANCESea cucumbers are major inhabitants in hadal trenches. They collect microbes in surface sediment and remain tolerant against potential pathogenic bacteria and viruses. This study presents the genome of endosymbiotic spiroplasmas in the gut of a sea cucumber captured in the Mariana Trench. The extreme reduction of the genome and loss of essential metabolic pathways strongly support its endosymbiotic lifestyle. Moreover, a considerable part of the genome was occupied by a CRISPR/Cas system to provide immunity against viruses and antimicrobial toxin-encoding genes for the degradation of microbes. This novel species ofSpiroplasmais probably an important protective symbiont for the sea cucumbers in the hadal zone.

scholarly journals Trichoderma atroviride Transcriptional Regulator Xyr1 Supports the Induction of Systemic Resistance in Plants

2014 ◽  
Vol 80 (17) ◽  
pp. 5274-5281 ◽  
Author(s):  
Barbara Reithner ◽  
Astrid R. Mach-Aigner ◽  
Alfredo Herrera-Estrella ◽  
Robert L. Mach
Keyword(s):  
Regulatory Protein ◽  
Transcriptional Regulator ◽  
Systemic Resistance ◽  
Accessory Cell ◽  
Transcript Analysis ◽  
Trichoderma Atroviride ◽  
Cell Wall Degrading Enzymes ◽  
Content Type ◽  
Precise Role

ABSTRACTAs a result of a transcriptome-wide analysis of the ascomyceteTrichoderma atroviride, mycoparasitism-related genes were identified; of these, 13 genes were further investigated for differential expression.In silicoanalysis of the upstream regulatory regions of these genes pointed to xylanase regulator 1 (Xyr1) as a putatively involved regulatory protein. Transcript analysis of thexyr1gene ofT. atroviridein confrontation with other fungi allowed us to determine thatxyr1levels increased during mycoparasitism. To gain knowledge about the precise role of Xyr1 in the mycoparasitic process, the corresponding gene was deleted from theT. atroviridegenome. This resulted in strong reductions in the transcript levels ofaxe1andswo1, which encode accessory cell wall-degrading enzymes considered relevant for mycoparasitism. We also analyzed the role of Xyr1 in theTrichoderma-Arabidopsisinteraction, finding that the plant response elicited byT. atrovirideis delayed if Xyr1 is missing in the fungus.

scholarly journals Role of Transcription Factor CaNdt80p in Cell Separation, Hyphal Growth, and Virulence in Candida albicans

2010 ◽  
Vol 9 (4) ◽  
pp. 634-644 ◽  
Author(s):  
Adnane Sellam ◽  
Christopher Askew ◽  
Elias Epp ◽  
Faiza Tebbji ◽  
Alaka Mullick ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Candida Albicans ◽  
Cell Separation ◽  
Hyphal Growth ◽  
Functional Domain ◽  
Transcription Factor Family ◽  
Content Type ◽  
Genes Encoding

ABSTRACT The NDT80/PhoG transcription factor family includes ScNdt80p, a key modulator of the progression of meiotic division in Saccharomyces cerevisiae. In Candida albicans, a member of this family, CaNdt80p, modulates azole sensitivity by controlling the expression of ergosterol biosynthesis genes. We previously demonstrated that CaNdt80p promoter targets, in addition to ERG genes, were significantly enriched in genes related to hyphal growth. Here, we report that CaNdt80p is indeed required for hyphal growth in response to different filament-inducing cues and for the proper expression of genes characterizing the filamentous transcriptional program. These include noteworthy genes encoding cell wall components, such as HWP1, ECE1, RBT4, and ALS3. We also show that CaNdt80p is essential for the completion of cell separation through the direct transcriptional regulation of genes encoding the chitinase Cht3p and the cell wall glucosidase Sun41p. Consistent with their hyphal defect, ndt80 mutants are avirulent in a mouse model of systemic candidiasis. Interestingly, based on functional-domain organization, CaNdt80p seems to be a unique regulator characterizing fungi from the CTG clade within the subphylum Saccharomycotina. Therefore, this study revealed a new role of the novel member of the fungal NDT80 transcription factor family as a regulator of cell separation, hyphal growth, and virulence.

scholarly journals CodY-Mediated c-di-GMP-Dependent Inhibition of Mammalian Cell Invasion in Listeria monocytogenes

2017 ◽  
Vol 200 (5) ◽  
Author(s):  
Ahmed M. Elbakush ◽  
Kurt W. Miller ◽  
Mark Gomelsky
Keyword(s):  
Transcription Factor ◽  
Listeria Monocytogenes ◽  
Mammalian Cell ◽  
Cell Invasion ◽  
Mammalian Cells ◽  
Pathogenic Bacteria ◽  
Second Messenger ◽  
Content Type ◽  
Branched Chain

ABSTRACT Elevated levels of the second messenger c-di-GMP suppress virulence in diverse pathogenic bacteria, yet mechanisms are poorly characterized. In the foodborne pathogen Listeria monocytogenes , high c-di-GMP levels inhibit mammalian cell invasion. Here, we show that invasion is impaired because of the decreased expression levels of internalin genes whose products are involved in invasion. We further show that at high c-di-GMP levels, the expression of the entire virulence regulon is suppressed, and so is the expression of the prfA gene encoding the master activator of the virulence regulon. Analysis of mechanisms controlling prfA expression pointed to the transcription factor CodY as a c-di-GMP-sensitive component. In high-c-di-GMP strains, codY gene expression is decreased, apparently due to the lower activity of CodY, which functions as an activator of codY transcription. We found that listerial CodY does not bind c-di-GMP in vitro and therefore investigated whether c-di-GMP levels affect two known cofactors of listerial CodY, branched-chain amino acids and GTP. Our manipulation of branched-chain amino acid levels did not perturb the c-di-GMP effect; however, our replacement of listerial CodY with the streptococcal CodY homolog, whose activity is GTP independent, abolished the c-di-GMP effect. The results of this study suggest that elevated c-di-GMP levels decrease the activity of the coordinator of metabolism and virulence, CodY, possibly via lower GTP levels, and that decreased CodY activity suppresses L. monocytogenes virulence by the decreased expression of the PrfA virulence regulon. IMPORTANCE Listeria monocytogenes is a pathogen causing listeriosis, a disease responsible for the highest mortality rate among foodborne diseases. Understanding how the virulence of this pathogen is regulated is important for developing treatments to decrease the frequency of listerial infections in susceptible populations. In this study, we describe the mechanism through which elevated levels of the second messenger c-di-GMP inhibit listerial invasion in mammalian cells. Inhibition is caused by the decreased activity of the transcription factor CodY that coordinates metabolism and virulence.

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