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1.
Nat Commun ; 14(1): 7519, 2023 11 18.
Article in English | MEDLINE | ID: mdl-37980337

ABSTRACT

The Mycobacterium tuberculosis complex (MTBC) includes several human- and animal-adapted pathogens. It is thought to have originated in East Africa from a recombinogenic Mycobacterium canettii-like ancestral pool. Here, we describe the discovery of a clinical tuberculosis strain isolated in Ethiopia that shares archetypal phenotypic and genomic features of M. canettii strains, but represents a phylogenetic branch much closer to the MTBC clade than to the M. canettii strains. Analysis of genomic traces of horizontal gene transfer in this isolate and previously identified M. canettii strains indicates a persistent albeit decreased recombinogenic lifestyle near the emergence of the MTBC. Our findings support that the MTBC emergence from its putative free-living M. canettii-like progenitor is evolutionarily very recent, and suggest the existence of a continuum of further extant derivatives from ancestral stages, close to the root of the MTBC, along the Great Rift Valley.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Humans , Phylogeny , Ethiopia , Tuberculosis/microbiology , Africa, Eastern
2.
Microbiol Spectr ; : e0083323, 2023 Aug 29.
Article in English | MEDLINE | ID: mdl-37642428

ABSTRACT

Genome evolution, and more specifically gene duplication, is a key process shaping host-microorganism interaction. The conserved paralogs usually provide an advantage to the bacterium to thrive. If not, these genes become pseudogenes and disappear. Here, we show that during the emergence of the genus Dickeya, the gene encoding the porin OmpF was duplicated. Our results show that the ompF2 expression is deleterious to the virulence of Dickeya dadantii, the agent causing soft rot disease. Interestingly, ompF2 is regulated while ompF is constitutive but activated by the EnvZ-OmpR two-component system. In vitro, acidic pH triggers the system. The pH measured in four eudicotyledons increased from an initial pH of 5.5 to 7 within 8 h post-infection. Then, the pH decreased to 5.5 at 10 h post-infection and until full maceration of the plant tissue. Yet, the production of phenolic acids by the plant's defenses prevents the activation of the EnvZ-OmpR system to avoid the ompF2 expression even though environmental conditions should trigger this system. We highlight that gene duplication in a pathogen is not automatically an advantage for the infectious process and that, there was a need for our model organism to adapt its genetic regulatory networks to conserve these duplicated genes. IMPORTANCE Dickeya species cause various diseases in a wide range of crops and ornamental plants. Understanding the molecular program that allows the bacterium to colonize the plant is key to developing new pest control methods. Unlike other enterobacterial pathogens, Dickeya dadantii, the causal agent of soft rot disease, does not require the EnvZ-OmpR system for virulence. Here, we showed that during the emergence of the genus Dickeya, the gene encoding the porin OmpF was duplicated and that the expression of ompF2 was deleterious for virulence. We revealed that while the EnvZ-OmpR system was activated in vitro by acidic pH and even though the pH was acidic when the plant is colonized, this system was repressed by phenolic acid (generated by the plant's defenses). These results provide a unique- biologically relevant-perspective on the consequence of gene duplication and the adaptive nature of regulatory networks to retain the duplicated gene.

3.
Nat Commun ; 11(1): 2917, 2020 06 09.
Article in English | MEDLINE | ID: mdl-32518235

ABSTRACT

The human- and animal-adapted lineages of the Mycobacterium tuberculosis complex (MTBC) are thought to have expanded from a common progenitor in Africa. However, the molecular events that accompanied this emergence remain largely unknown. Here, we describe two MTBC strains isolated from patients with multidrug resistant tuberculosis, representing an as-yet-unknown lineage, named Lineage 8 (L8), seemingly restricted to the African Great Lakes region. Using genome-based phylogenetic reconstruction, we show that L8 is a sister clade to the known MTBC lineages. Comparison with other complete mycobacterial genomes indicate that the divergence of L8 preceded the loss of the cobF genome region - involved in the cobalamin/vitamin B12 synthesis - and gene interruptions in a subsequent common ancestor shared by all other known MTBC lineages. This discovery further supports an East African origin for the MTBC and provides additional molecular clues on the ancestral genome reduction associated with adaptation to a pathogenic lifestyle.


Subject(s)
Genome, Bacterial , Mycobacterium tuberculosis/classification , Tuberculosis, Multidrug-Resistant/microbiology , Aged , DNA, Bacterial/genetics , Evolution, Molecular , Genetic Variation , Genomics , Genotype , Humans , Likelihood Functions , Limit of Detection , Male , Mutation , Mycobacterium tuberculosis/isolation & purification , Phenotype , Phylogeny , Rifampin/pharmacology , Rwanda , Uganda
4.
PLoS Genet ; 15(11): e1008497, 2019 11.
Article in English | MEDLINE | ID: mdl-31747390

ABSTRACT

The lipopolysaccharide O-antigen structure expressed by the European Helicobacter pylori model strain G27 encompasses a trisaccharide, an intervening glucan-heptan and distal Lewis antigens that promote immune escape. However, several gaps still remain in the corresponding biosynthetic pathway. Here, systematic mutagenesis of glycosyltransferase genes in G27 combined with lipopolysaccharide structural analysis, uncovered HP0102 as the trisaccharide fucosyltransferase, HP1283 as the heptan transferase, and HP1578 as the GlcNAc transferase that initiates the synthesis of Lewis antigens onto the heptan motif. Comparative genomic analysis of G27 lipopolysaccharide biosynthetic genes in strains of different ethnic origin revealed that East-Asian strains lack the HP1283/HP1578 genes but contain an additional copy of HP1105 and JHP0562. Further correlation of different lipopolysaccharide structures with corresponding gene contents led us to propose that the second copy of HP1105 and the JHP0562 may function as the GlcNAc and Gal transferase, respectively, to initiate synthesis of the Lewis antigen onto the Glc-Trio-Core in East-Asian strains lacking the HP1283/HP1578 genes. In view of the high gastric cancer rate in East Asia, the absence of the HP1283/HP1578 genes in East-Asian H. pylori strains warrants future studies addressing the role of the lipopolysaccharide heptan in pathogenesis.


Subject(s)
Helicobacter Infections/genetics , Lipopolysaccharides/genetics , O Antigens/genetics , Stomach Neoplasms/genetics , Asian People , Fucosyltransferases/genetics , Fucosyltransferases/immunology , Glucans/genetics , Glycosyltransferases/genetics , Glycosyltransferases/immunology , Helicobacter Infections/immunology , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Helicobacter pylori/genetics , Helicobacter pylori/immunology , Helicobacter pylori/pathogenicity , Humans , Lewis Blood Group Antigens/genetics , Lewis Blood Group Antigens/immunology , Lipopolysaccharides/chemistry , Lipopolysaccharides/immunology , Mutagenesis , O Antigens/immunology , Stomach Neoplasms/epidemiology , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology
5.
Front Immunol ; 10: 1830, 2019.
Article in English | MEDLINE | ID: mdl-31428104

ABSTRACT

Yersinioses caused by Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica are significant concerns in human and veterinary health. The link between virulence and the potent LcrV antigen has prompted the latter's selection as a major component of anti-Yersinia vaccines. Here, we report that (i) the group of Yersinia species encompassing Y. pestis and Y. pseudotuberculosis produces at least five different clades of LcrV and (ii) vaccination of mice with an LcrV-secreting Lactococcus lactis only protected against Yersinia strains producing the same LcrV clade as that of used for vaccination. By vaccinating with engineered LcrVs and challenging mice with strains producing either type of LcrV or a LcrV mutated for regions of interest, we highlight key polymorphic residues responsible for the absence of cross-protection. Our results show that an anti-LcrV-based vaccine should contain multiple LcrV clades if protection against the widest possible array of Yersinia strains is sought.


Subject(s)
Antigens, Bacterial/immunology , Bacterial Vaccines/immunology , Lactococcus lactis/immunology , Pore Forming Cytotoxic Proteins/immunology , Yersinia pestis/immunology , Yersinia pseudotuberculosis/immunology , Animals , Antibodies, Bacterial/immunology , Cross Protection/immunology , Disease Models, Animal , Female , Mice , Mice, Inbred BALB C , Vaccination/methods , Virulence/immunology , Yersinia Infections/immunology
6.
PLoS Pathog ; 13(11): e1006752, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29176894

ABSTRACT

The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species. Here, we sought to explore whether such ancient HGT played a part in M. tuberculosis evolution towards pathogenicity. We were interested by a HGT-acquired M. tuberculosis-specific gene set, namely moaA1-D1, which is involved in the biosynthesis of the molybdenum cofactor. Horizontal acquisition of this gene set was striking because homologues of these moa genes are present all across the Mycobacterium genus, including in M. tuberculosis. Here, we discovered that, unlike their paralogues, the moaA1-D1 genes are strongly induced under hypoxia. In vitro, a M. tuberculosis moaA1-D1-null mutant has an impaired ability to respire nitrate, to enter dormancy and to survive in oxygen-limiting conditions. Conversely, heterologous expression of moaA1-D1 in the phylogenetically closest non-TB mycobacterium, Mycobacterium kansasii, which lacks these genes, improves its capacity to respire nitrate and grants it with a marked ability to survive oxygen depletion. In vivo, the M. tuberculosis moaA1-D1-null mutant shows impaired survival in hypoxic granulomas in C3HeB/FeJ mice, but not in normoxic lesions in C57BL/6 animals. Collectively, our results identify a novel pathway required for M. tuberculosis resistance to host-imposed stress, namely hypoxia, and provide evidence that ancient HGT bolstered M. tuberculosis evolution from an environmental species towards a pervasive human-adapted pathogen.


Subject(s)
Coenzymes/biosynthesis , Gene Transfer, Horizontal , Metalloproteins/biosynthesis , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , Oxygen/metabolism , Tuberculosis/microbiology , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Female , Gene Expression Regulation, Bacterial , Humans , Hypoxia/metabolism , Hypoxia/microbiology , Mice , Mice, Inbred C57BL , Molybdenum Cofactors , Mycobacterium/genetics , Mycobacterium/metabolism , Nitrates/metabolism , Pteridines , Tuberculosis/metabolism
7.
Infect Immun ; 83(9): 3638-47, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26150539

ABSTRACT

The opgGH operon encodes glucosyltransferases that synthesize osmoregulated periplasmic glucans (OPGs) from UDP-glucose, using acyl carrier protein (ACP) as a cofactor. OPGs are required for motility, biofilm formation, and virulence in various bacteria. OpgH also sequesters FtsZ in order to regulate cell size according to nutrient availability. Yersinia pestis (the agent of flea-borne plague) lost the opgGH operon during its emergence from the enteropathogen Yersinia pseudotuberculosis. When expressed in OPG-negative strains of Escherichia coli and Dickeya dadantii, opgGH from Y. pseudotuberculosis restored OPGs synthesis, motility, and virulence. However, Y. pseudotuberculosis did not produce OPGs (i) under various growth conditions or (ii) when overexpressing its opgGH operon, its galUF operon (governing UDP-glucose), or the opgGH operon or Acp from E. coli. A ΔopgGH Y. pseudotuberculosis strain showed normal motility, biofilm formation, resistance to polymyxin and macrophages, and virulence but was smaller. Consistently, Y. pestis was smaller than Y. pseudotuberculosis when cultured at ≥ 37°C, except when the plague bacillus expressed opgGH. Y. pestis expressing opgGH grew normally in serum and within macrophages and was fully virulent in mice, suggesting that small cell size was not advantageous in the mammalian host. Lastly, Y. pestis expressing opgGH was able to infect Xenopsylla cheopis fleas normally. Our results suggest an evolutionary scenario whereby an ancestral Yersinia strain lost a factor required for OPG biosynthesis but kept opgGH (to regulate cell size). The opgGH operon was presumably then lost because OpgH-dependent cell size control became unnecessary.


Subject(s)
Bacterial Proteins/genetics , Evolution, Molecular , Yersinia pestis/pathogenicity , Yersinia pseudotuberculosis/genetics , Yersinia pseudotuberculosis/pathogenicity , Animals , Blotting, Western , Disease Models, Animal , Gene Deletion , Glucans/biosynthesis , Glucans/genetics , Mice , Operon/genetics , Periplasmic Proteins/biosynthesis , Periplasmic Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction
8.
J Infect Dis ; 210(9): 1367-75, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-24813471

ABSTRACT

Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2-component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues.


Subject(s)
Bacterial Outer Membrane Proteins/physiology , Plague/microbiology , Yersinia pestis/physiology , Animals , Complement System Proteins/immunology , Female , Immunity, Innate , Macrophages/microbiology , Mice , Rats , Reverse Transcriptase Polymerase Chain Reaction , Yersinia pestis/immunology , Yersinia pestis/pathogenicity
9.
Int J Syst Evol Microbiol ; 63(Pt 10): 3927-3929, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23919959

ABSTRACT

The 16S rRNA gene sequences of Pasteurella lymphangitidis, Yersinia pseudotuberculosis and Yersinia pestis were found to be identical and multilocus sequence analysis could not discriminate between the three species. The susceptibility to a Y. pseudotuberculosis phage and the presence of the Y. pseudotuberculosis-specific invasin gene in P. lymphangitidis indicate that the latter should be reclassified as Y. pseudotuberculosis.


Subject(s)
Pasteurella/classification , Yersinia pseudotuberculosis/classification , Bacterial Typing Techniques , Genes, Bacterial , Molecular Sequence Data , Multilocus Sequence Typing , Pasteurella/genetics , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Yersinia pseudotuberculosis/genetics
10.
Nat Genet ; 45(2): 172-9, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23291586

ABSTRACT

Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5× coverage), 454/Roche (13-18× coverage) and/or Illumina DNA sequencing (45-105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved.


Subject(s)
Adaptation, Biological/genetics , Adaptation, Biological/immunology , Evolution, Molecular , Genetic Variation , Genome, Bacterial/genetics , Mycobacterium tuberculosis/genetics , Phylogeny , Adaptation, Biological/physiology , Animals , Base Sequence , Cluster Analysis , Genomics , Inverted Repeat Sequences/genetics , Lung/virology , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Mycobacterium tuberculosis/classification , Mycobacterium tuberculosis/pathogenicity , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, DNA , Species Specificity , Spleen/virology , Virulence
11.
Gen Hosp Psychiatry ; 35(5): 574.e7-8, 2013.
Article in English | MEDLINE | ID: mdl-22959418

ABSTRACT

OBJECTIVE: Stuttering is a frequent side effect of many psychotropic drugs, particularly antidepressants. METHOD: This is a case report of a woman presenting with stuttering after starting bupropion treatment for her depression. RESULTS: The patient's stuttering resolved after discontinuing the bupropion. CONCLUSION: Neuroimaging and pharmacological studies have implicated dopamine in the pathophysiology of stuttering. Bupropion's ability to increase dopamine in the frontal cortex was suspected to have been involved in this patient's stuttering. However, further research is needed before causality can be assured.


Subject(s)
Antidepressive Agents, Second-Generation/adverse effects , Bupropion/adverse effects , Stuttering/chemically induced , Antidepressive Agents, Second-Generation/therapeutic use , Bupropion/therapeutic use , Depressive Disorder, Major/drug therapy , Female , Humans , Middle Aged
12.
Int J Med Microbiol ; 301(2): 105-16, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20951640

ABSTRACT

Although Yersinia pestis and Yersinia pseudotuberculosis are genetically very similar (97% nucleotide sequence identity for most of the chromosomal genes), they exhibit very different patterns of infection. Y. pestis causes plague which is usually fatal in the absence of treatment, whereas Y. pseudotuberculosis generally triggers non-life-threatening intestinal symptoms. This drastic difference in pathogenicity may result from the acquisition of a few species-specific genes, but also from differences in their transcriptional regulation networks. In this study, we performed an in silico comparative whole-genome transcriptome analysis of Y. pestis and Y. pseudotuberculosis grown in parallel under 8 distinct conditions to determine whether they exhibit differences in their regulatory networks. In this analysis, 304 genes common to both species were found to display significant inter-species differences in transcriptional levels, with 91% of them being more expressed in Y. pestis. Remarkably, 3 major virulence determinants conserved in the 2 species (the pYV virulence plasmid, the High Pathogenicity Island, and the ail locus) were among the genes more expressed in Y. pestis. Furthermore, the induction at 37°C of pYV-borne genes was considerably greater in Y. pestis than in Y. pseudotuberculosis. Conversely, the rovA transcriptional regulator gene was more transcribed in Y. pseudotuberculosis. We also performed a clustering analysis of the transcriptome data of both Y. pestis and Y. pseudotuberculosis, which allowed to group genes according to their expression profiles. This analysis identified groups of genes with unknown functions which, based on regulation patterns similar to those of known virulence genes, are potential new virulence determinants in Y. pestis. In conclusion, this is the first comparative analysis at the whole-genome level of the transcription profiles of Y. pestis and Y. pseudotuberculosis. Our results suggest that the higher pathogenicity of the plague bacillus may not only result from the acquisition of new genetic material, but also from a higher expression level of common crucial virulence genes. This in silico analysis thus opens new avenues for investigating Y. pestis gain of pathogenicity and new potential virulence factors.


Subject(s)
Gene Expression Profiling , Gene Expression , Virulence Factors/biosynthesis , Yersinia pestis/genetics , Yersinia pseudotuberculosis/genetics , Cluster Analysis , Genome, Bacterial , Humans , Virulence
13.
Microbiology (Reading) ; 155(Pt 7): 2168-2181, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19389764

ABSTRACT

During the course of its infection of the mammalian digestive tract, the entero-invasive, Gram-negative bacterium Yersinia pseudotuberculosis must overcome various hostile living conditions (notably, iron starvation and the presence of antimicrobial compounds produced in situ). We have previously reported that in vitro bacterial growth during iron deprivation raises resistance to the antimicrobial peptide polymyxin B; here, we show that this phenotype is mediated by a chromosomal gene (YPTB0333) encoding a transcriptional regulator from the LysR family. We determined that the product of YPTB0333 is a pleiotropic regulator which controls (in addition to its own expression) genes encoding the Yfe iron-uptake system and polymyxin B resistance. Lastly, by using a mouse model of oral infection, we demonstrated that YPTB0333 is required for colonization of Peyer's patches and mesenteric lymph nodes by Y. pseudotuberculosis.


Subject(s)
Iron/metabolism , Polymyxin B/pharmacology , Transcription Factors/biosynthesis , Yersinia pseudotuberculosis Infections/microbiology , Yersinia pseudotuberculosis , Animals , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Gene Expression Regulation, Bacterial , Genes, Bacterial , Mice , Operator Regions, Genetic , Peyer's Patches/microbiology , Protein Engineering , Transcription Factors/deficiency , Transcription Factors/genetics , Virulence , Yersinia enterocolitica/drug effects , Yersinia enterocolitica/metabolism , Yersinia pseudotuberculosis/drug effects , Yersinia pseudotuberculosis/metabolism , Yersinia pseudotuberculosis/pathogenicity
14.
BMC Microbiol ; 8: 211, 2008 Dec 03.
Article in English | MEDLINE | ID: mdl-19055764

ABSTRACT

BACKGROUND: In man, infection by the Gram-negative enteropathogen Yersinia pseudotuberculosis is usually limited to the terminal ileum. However, in immunocompromised patients, the microorganism may disseminate from the digestive tract and thus cause a systemic infection with septicemia. RESULTS: To gain insight into the metabolic pathways and virulence factors expressed by the bacterium at the blood stage of pseudotuberculosis, we compared the overall gene transcription patterns (the transcriptome) of bacterial cells cultured in either human plasma or Luria-Bertani medium. The most marked plasma-triggered metabolic consequence in Y. pseudotuberculosis was the switch to high glucose consumption, which is reminiscent of the acetogenic pathway (known as "glucose overflow") in Escherichia coli. However, upregulation of the glyoxylate shunt enzymes suggests that (in contrast to E. coli) acetate may be further metabolized in Y. pseudotuberculosis. Our data also indicate that the bloodstream environment can regulate major virulence genes (positively or negatively); the yadA adhesin gene and most of the transcriptional units of the pYV-encoded type III secretion apparatus were found to be upregulated, whereas transcription of the pH6 antigen locus was strongly repressed. CONCLUSION: Our results suggest that plasma growth of Y. pseudotuberculosis is responsible for major transcriptional regulatory events and prompts key metabolic reorientations within the bacterium, which may in turn have an impact on virulence.


Subject(s)
Gene Expression Regulation, Bacterial , Plasma/microbiology , Yersinia pseudotuberculosis/genetics , Yersinia pseudotuberculosis/pathogenicity , Adhesins, Bacterial/genetics , Adhesins, Bacterial/metabolism , Citric Acid Cycle/genetics , Culture Media , Gene Expression Profiling , Glucose/metabolism , Glycolysis/genetics , Humans , Iron/metabolism , Up-Regulation , Virulence , Yersinia pseudotuberculosis/growth & development , Yersinia pseudotuberculosis Infections/metabolism , Yersinia pseudotuberculosis Infections/microbiology
15.
Int J Med Microbiol ; 298(3-4): 193-207, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17765656

ABSTRACT

Two-component regulatory systems (2CSs) typically comprise a sensor kinase and a response regulator that, in concert, monitor the concentration of particular extracellular factors and mediate the transcription of specific genes accordingly. As such, 2CSs play an important role in the regulation of bacterial pathogenesis. On the basis of genome-wide in silico analysis, the Gram-negative enteropathogenic bacterium Yersinia pseudotuberculosis is thought to encode 24 complete 2CSs. In the present work, we mutated the corresponding 2CS response regulator-encoding genes in Y. pseudotuberculosis strain 32777 and assessed the in vitro resistance of each mutant to the various types of stress encountered by Yersinia cells in the digestive tract. Eight of the generated regulatory mutants (phoP, ompR, pmrA, ntrC-, arcA-, rstA-, rcsB-, and yfhA-like mutants) showed significant changes in tolerance towards at least one type of stress, when compared with the wild-type strain. Of these eight, four (ompR, phoP, rstA-, and yfhA-like mutants) were found to be less virulent than the wild type in the BALB/c mouse model. Although some mutant phenotypes were consistent with those (when known) of the corresponding, putative ortholog mutants in other pathogenic species, several response regulators behaved differently in Y. pseudotuberculosis; these included the PmrA, PhoP, and ArcA-like response regulators, which were found to control bile salt resistance in a manner different from that observed in Salmonella. Hence, in addition to genome evolution, transcriptional network remodeling may be a major cause of phenotypic adaptation (and thus species divergence) in Y. pseudotuberculosis.


Subject(s)
Regulon/physiology , Yersinia pseudotuberculosis/genetics , Animals , Bacterial Proteins/physiology , Female , Mice , Mice, Inbred BALB C , Mutation , Phenotype , Transcription Factors/physiology , Virulence , Yersinia pseudotuberculosis/pathogenicity
16.
Adv Exp Med Biol ; 603: 145-55, 2007.
Article in English | MEDLINE | ID: mdl-17966411

ABSTRACT

In bacteria, the most rapid and efficient means of adapting gene transcription to extracellular stresses often involves sophisticated systems referred to as two-component systems (2CSs). Although highly conserved throughout the bacterial world, some of these systems may control distinct cell events and have differing contributions to virulence, depending on the species considered. This chapter summarizes the work performed by our group--from the initial PhoP-PhoQ and PmrA-PmrB studies to the most recent genome-scale preliminary analyses--in an attempt to highlight the contribution of 2CS regulon plasticity to the acquisition of some of Yersinia pseudotuberculosis' specific features.


Subject(s)
Regulon , Yersinia pseudotuberculosis/genetics , Bacterial Proteins/genetics , Enterobacteriaceae/genetics , Gene Expression Regulation, Bacterial , Models, Genetic , Mutation , Operon , Phenotype , Signal Transduction , Species Specificity , Transcription Factors/genetics , Virulence/genetics , Yersinia pseudotuberculosis/pathogenicity , Yersinia pseudotuberculosis/physiology
17.
Adv Exp Med Biol ; 603: 361-6, 2007.
Article in English | MEDLINE | ID: mdl-17966432

ABSTRACT

Microbial pathogens have developed various stratagems for modulating and/or circumventing the host's innate and adaptive immunity. Hence, certain virulence factors can be viewed as potential therapeutic agents for human immunopathological diseases. This is the case for virulence plasmid-encoded proteins from pathogenic Yersiniae that inhibit the host's inflammatory response by interfering with various cellular signaling pathways.


Subject(s)
Inflammation/therapy , Virulence Factors/therapeutic use , Yersinia/immunology , Animals , Antigens, Bacterial/genetics , Antigens, Bacterial/immunology , Colitis/immunology , Colitis/prevention & control , Humans , Inflammation/immunology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/therapy , Lactococcus lactis/genetics , Lactococcus lactis/immunology , Mice , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/immunology , Trinitrobenzenesulfonic Acid/toxicity , Yersinia/genetics , Yersinia/pathogenicity
18.
Microbiology (Reading) ; 153(Pt 9): 3112-3124, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17768254

ABSTRACT

Yersinia pestis is the aetiologic agent of plague. Without appropriate treatment, the pathogen rapidly causes septicaemia, the terminal and fatal phase of the disease. In order to identify bacterial genes which are essential during septicaemic plague in humans, we performed a transcriptome analysis on the fully virulent Y. pestis CO92 strain grown in either decomplemented human plasma or Luria-Bertani medium, incubated at either 28 or 37 degrees C and harvested at either the mid-exponential or the stationary growth phase. Y. pestis genes involved in 12 iron-acquisition systems and one iron-storage system (bfr, bfd) were specifically induced in human plasma. Of these, the ybt and tonB genes (encoding the yersiniabactin siderophore virulence factor and the siderophore transporter, respectively) were induced at 37 degrees C, i.e. under conditions mimicking the mammalian environment. Growth in human plasma also upregulated genes involved in the synthesis of five fimbrial-like structures (including the Psa virulence factor), and in purine/pyrimidine metabolism (the nrd genes). Genes known to play a role in the virulence of several bacterial pathogens (such as those encoding the Lpp lipoprotein and non-iron metal-uptake proteins) were induced in human plasma, during either the exponential or the stationary phase. Finally, 120 genes encoding proteins of unknown function were upregulated in human plasma. Eleven of these genes were specifically transcribed at 37 degrees C and may thus represent new virulence factors that are important during the septicaemic phase of human plague.


Subject(s)
Bacteremia/microbiology , Bacterial Proteins/metabolism , Gene Expression Regulation, Bacterial , Genome, Bacterial , Oligonucleotide Array Sequence Analysis/methods , Plasma/microbiology , Proteome , Yersinia pestis/pathogenicity , Bacterial Proteins/genetics , Culture Media , Gene Expression Profiling , Humans , Plague/microbiology , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Yersinia pestis/genetics , Yersinia pestis/growth & development , Yersinia pestis/metabolism
19.
Gastroenterology ; 133(3): 862-74, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17678918

ABSTRACT

BACKGROUND & AIMS: The low calcium response V (LcrV) protein synthesized by gram-negative, pathogenic yersiniae participates in bacterial evasion of the host's innate immune response by stimulating synthesis of the anti-inflammatory interleukin (IL)-10 and preventing the activation of proinflammatory cytokines. METHODS: We genetically engineered the food-grade bacterium Lactococcus lactis to secrete the LcrV protein from the enteropathogenic species Yersinia pseudotuberculosis. The protective and therapeutic potential of orally administered LcrV-secreting L lactis was evaluated in 2 models of acute experimental colitis (induced by trinitrobenzene sulfonic acid [TNBS] and dextran sodium sulfate [DSS], respectively) in wild-type and knockout mice. RESULTS: Oral administration of LcrV-secreting L lactis led to active delivery of LcrV and induction of IL-10 (via a Toll-like receptor 2-dependent pathway) in the colon and prevented TNBS-induced colitis, in contrast to the L lactis control not producing LcrV. Down-regulation of tissue inflammatory markers correlated well with the reduction in damage to the colonic mucosa. In contrast, TNBS-induced colitis was not prevented in IL-10(-/-) mice pretreated with LcrV-secreting L lactis, thus showing that IL-10 is required for LcrV protection. Administration of LcrV-secreting L lactis also proved to be very effective in preventing and treating acute DSS-induced colitis. CONCLUSIONS: LcrV-secreting L lactis decreased experimentally induced intestinal inflammation in 2 murine models of colitis. This novel approach highlights the potential of using pathogen-derived immunomodulating molecules in vivo as novel therapeutics for inflammatory bowel diseases.


Subject(s)
Antigens, Bacterial/metabolism , Antigens, Bacterial/therapeutic use , Colitis/drug therapy , Colitis/prevention & control , Lactococcus lactis/metabolism , Pore Forming Cytotoxic Proteins/metabolism , Pore Forming Cytotoxic Proteins/therapeutic use , Administration, Oral , Animals , Antigens, Bacterial/administration & dosage , Cells, Cultured , Colitis/chemically induced , Dextran Sulfate , Disease Models, Animal , Female , Interleukin-10/genetics , Interleukin-10/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Pore Forming Cytotoxic Proteins/administration & dosage , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Trinitrobenzenesulfonic Acid
20.
Curr Issues Mol Biol ; 7(2): 151-77, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16053248

ABSTRACT

In response to the ever-present need to adapt to environmental stress, bacteria have evolved complex (and often overlapping) regulatory networks that respond to various changes in growth conditions, including entry into the host. The expression of most bacterial virulence factors is regulated; thus the question of how bacteria orchestrate this process has become a recurrent research theme for every bacterial pathogen, and the three pathogenic Yersinia are no exception. The earliest studies of regulation in these species were prompted by the characterization of plasmid-encoded virulence determinants, and those conducted since have continued to focus on the principal aspects of virulence in these pathogens. Most Yersinia virulence factors are thermally regulated, and are active at either 28 degrees C (the optimal growth temperature) or 37 degrees C (the host temperature). However, regulation by this omnipresent thermal stimulus occurs through a wide variety of mechanisms, which generally act in conjunction with (or are modulated by) additional controls for other environmental cues such as pH, ion concentration, nutrient availability, osmolarity, oxygen tension and DNA damage. Yersinia's recent entry into the genome sequencing era has given scientists the opportunity to study these regulators on a genome-wide basis. This has prompted the first attempts to establish links between the presence or absence of regulatory elements and the three pathogenic species' respective lifestyles and degrees of virulence.


Subject(s)
Gene Expression Regulation, Bacterial , Transcription, Genetic , Yersinia/genetics , Antigens, Bacterial/biosynthesis , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Enterotoxins/biosynthesis , Enterotoxins/genetics , Genome, Bacterial , Temperature , Virulence/genetics , Virulence Factors/genetics , Virulence Factors/metabolism , Yersinia/immunology , Yersinia/metabolism , Yersinia/pathogenicity
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