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Salmonella bongori Provides Insights into the Evolution of the Salmonellae  [PDF]
Maria Fookes ?,Gunnar N. Schroeder ?,Gemma C. Langridge ?,Carlos J. Blondel,Caterina Mammina,Thomas R. Connor,Helena Seth-Smith,Georgios S. Vernikos,Keith S. Robinson,Mandy Sanders,Nicola K. Petty,Robert A. Kingsley,Andreas J. B?umler,Sean-Paul Nuccio,Inés Contreras,Carlos A. Santiviago,Duncan Maskell,Paul Barrow,Tom Humphrey,Antonino Nastasi,Mark Roberts,Gad Frankel,Julian Parkhill,Gordon Dougan,Nicholas R. Thomson
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002191
Abstract: The genus Salmonella contains two species, S. bongori and S. enterica. Compared to the well-studied S. enterica there is a marked lack of information regarding the genetic makeup and diversity of S. bongori. S. bongori has been found predominantly associated with cold-blooded animals, but it can infect humans. To define the phylogeny of this species, and compare it to S. enterica, we have sequenced 28 isolates representing most of the known diversity of S. bongori. This cross-species analysis allowed us to confidently differentiate ancestral functions from those acquired following speciation, which include both metabolic and virulence-associated capacities. We show that, although S. bongori inherited a basic set of Salmonella common virulence functions, it has subsequently elaborated on this in a different direction to S. enterica. It is an established feature of S. enterica evolution that the acquisition of the type III secretion systems (T3SS-1 and T3SS-2) has been followed by the sequential acquisition of genes encoding secreted targets, termed effectors proteins. We show that this is also true of S. bongori, which has acquired an array of novel effector proteins (sboA-L). All but two of these effectors have no significant S. enterica homologues and instead are highly similar to those found in enteropathogenic Escherichia coli (EPEC). Remarkably, SboH is found to be a chimeric effector protein, encoded by a fusion of the T3SS-1 effector gene sopA and a gene highly similar to the EPEC effector nleH from enteropathogenic E. coli. We demonstrate that representatives of these new effectors are translocated and that SboH, similarly to NleH, blocks intrinsic apoptotic pathways while being targeted to the mitochondria by the SopA part of the fusion. This work suggests that S. bongori has inherited the ancestral Salmonella virulence gene set, but has adapted by incorporating virulence determinants that resemble those employed by EPEC.
Lack of Effect of the Salmonella Deubiquitinase SseL on the NF-κB Pathway  [PDF]
Francisco S. Mesquita, David W. Holden, Nathalie Rolhion
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053064
Abstract: Intracellular replication of Salmonella enterica requires effector proteins translocated across the Salmonella-containing vacuolar membrane by Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). The SPI-2 T3SS effector SseL is a deubiquitinase that contributes to virulence in mice. Previous work has produced conflicting evidence as to the involvement of SseL in interference with the NF-κB pathway. To attempt to clarify these discrepancies, we compared mRNA levels in mouse primary bone marrow-derived macrophages infected with wild-type or sseL mutant strains using a genome-wide microarray. There was no detectable effect of loss of SseL on mRNA levels corresponding to any known NF-κB-regulated gene. In addition, there was no effect of SseL on (i) the activation or levels of both the canonical inhibitor of the NF-κB pathway (IκBα and phospho-IκBα), and the non-canonical NF-κB precursor p100/p52, (ii) the translocation of the NF-κB transcription factor p65 to the nucleus of infected macrophages and (iii) pro-inflammatory cytokines secretion. Furthermore, ectopic expression of SseL did not affect NF-κB activation in reporter cell lines. These results fail to support a role for SseL in the down-regulation of the host immune response and in particular the NF-κB pathway.
The Salmonella Deubiquitinase SseL Inhibits Selective Autophagy of Cytosolic Aggregates  [PDF]
Francisco S. Mesquita,Mair Thomas,Martin Sachse,António J. M. Santos,Rita Figueira,David W. Holden
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002743
Abstract: Cell stress and infection promote the formation of ubiquitinated aggregates in both non-immune and immune cells. These structures are recognised by the autophagy receptor p62/sequestosome 1 and are substrates for selective autophagy. The intracellular growth of Salmonella enterica occurs in a membranous compartment, the Salmonella-containing vacuole (SCV), and is dependent on effectors translocated to the host cytoplasm by the Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). Here, we show that bacterial replication is accompanied by the formation of ubiquitinated structures in infected cells. Analysis of bacterial strains carrying mutations in genes encoding SPI-2 T3SS effectors revealed that in epithelial cells, formation of these ubiquitinated structures is dependent on SPI-2 T3SS effector translocation, but is counteracted by the SPI-2 T3SS deubiquitinase SseL. In macrophages, both SPI-2 T3SS-dependent aggregates and aggresome-like induced structures (ALIS) are deubiquitinated by SseL. In the absence of SseL activity, ubiquitinated structures are recognized by the autophagy receptor p62, which recruits LC3 and targets them for autophagic degradation. We found that SseL activity lowers autophagic flux and favours intracellular Salmonella replication. Our data therefore show that there is a host selective autophagy response to intracellular Salmonella infection, which is counteracted by the deubiquitinase SseL.
Comparative Proteomic Analysis of the PhoP Regulon in Salmonella enterica Serovar Typhi Versus Typhimurium  [PDF]
Richelle C. Charles, Jason B. Harris, Michael R. Chase, Lauren M. Lebrun, Alaullah Sheikh, Regina C. LaRocque, Tanya Logvinenko, Sean M. Rollins, Abdullah Tarique, Elizabeth L. Hohmann, Ian Rosenberg, Bryan Krastins, David A. Sarracino, Firdausi Qadri, Stephen B. Calderwood, Edward T. Ryan
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006994
Abstract: Background S. Typhi, a human-restricted Salmonella enterica serovar, causes a systemic intracellular infection in humans (typhoid fever). In comparison, S. Typhimurium causes gastroenteritis in humans, but causes a systemic typhoidal illness in mice. The PhoP regulon is a well studied two component (PhoP/Q) coordinately regulated network of genes whose expression is required for intracellular survival of S. enterica. Methodology/Principal Findings Using high performance liquid chromatography mass spectrometry (HPLC-MS/MS), we examined the protein expression profiles of three sequenced S. enterica strains: S. Typhimurium LT2, S. Typhi CT18, and S. Typhi Ty2 in PhoP-inducing and non-inducing conditions in vitro and compared these results to profiles of phoP?/Q? mutants derived from S. Typhimurium LT2 and S. Typhi Ty2. Our analysis identified 53 proteins in S. Typhimurium LT2 and 56 proteins in S. Typhi that were regulated in a PhoP-dependent manner. As expected, many proteins identified in S. Typhi demonstrated concordant differential expression with a homologous protein in S. Typhimurium. However, three proteins (HlyE, STY1499, and CdtB) had no homolog in S. Typhimurium. HlyE is a pore-forming toxin. STY1499 encodes a stably expressed protein of unknown function transcribed in the same operon as HlyE. CdtB is a cytolethal distending toxin associated with DNA damage, cell cycle arrest, and cellular distension. Gene expression studies confirmed up-regulation of mRNA of HlyE, STY1499, and CdtB in S. Typhi in PhoP-inducing conditions. Conclusions/Significance This study is the first protein expression study of the PhoP virulence associated regulon using strains of Salmonella mutant in PhoP, has identified three Typhi-unique proteins (CdtB, HlyE and STY1499) that are not present in the genome of the wide host-range Typhimurium, and includes the first protein expression profiling of a live attenuated bacterial vaccine studied in humans (Ty800).
Identification and characterization of PhoP regulon members in Yersinia pestis biovar Microtus
Yingli Li, He Gao, Long Qin, Bei Li, Yanping Han, Zhaobiao Guo, Yajun Song, Junhui Zhai, Zongmin Du, Xiaoyi Wang, Dongsheng Zhou, Ruifu Yang
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-143
Abstract: By using gel mobility shift assay and quantitative RT-PCR, a total of 30 putative transcription units were characterized as direct PhoP targets. The primer extension assay was further used to determine the transcription start sites of 18 PhoP-dependent promoters and to localize the -10 and -35 elements. The DNase I footprinting was used to identify the PhoP-binding sites within 17 PhoP-dependent promoters, enabling the identification of PhoP box and matrix that both represented the conserved signals for PhoP recognition in Y. pestis. Data presented here providing a good basis for modeling PhoP-promoter DNA interactions that is crucial to the PhoP-mediated transcriptional regulation.The proven direct PhoP targets include nine genes encoding regulators and 21 genes or operons with functions of detoxification, protection against DNA damages, resistance to antimicrobial peptides, and adaptation to magnesium limitation. We can presume that PhoP is a global regulator that controls a complex regulatory cascade by a mechanism of not only directly controlling the expression of specific genes, but also indirectly regulating various cellular pathways by acting on a set of dedicated regulators. These results help us gain insights into the PhoP-dependent mechanisms by which Y. pestis survives the antibacterial strategies employed by host macrophages.Plague, caused by Yersinia pestis, is one of the most dangerous, infectious diseases in the world [1]. Y. pestis has the ability of survival and growth within na?ve macrophages both in vivo and in vitro [2,3]. It has been shown that Y. pestis is a facultative intracellular parasite that resides and grows within host macrophages during the early stages of infection [4]. Many virulence factors of Y. pestis have been tested for their ability to promote resistance to macrophage killing: pesticin, Pla, the pigmentation phenotype, and the plasmid pCD1-encoded type III secretion system, but they are all shown not to be required for bacteria
PhoP: A Missing Piece in the Intricate Puzzle of Mycobacterium tuberculosis Virulence  [PDF]
Jesús Gonzalo-Asensio, Serge Mostowy, Jose Harders-Westerveen, Kris Huygen, Rogelio Hernández-Pando, Jelle Thole, Marcel Behr, Brigitte Gicquel, Carlos Martín
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003496
Abstract: Inactivation of the transcriptional regulator PhoP results in Mycobacterium tuberculosis attenuation. Preclinical testing has shown that attenuated M. tuberculosis phoP mutants hold promise as safe and effective live vaccine candidates. We focused this study to decipher the virulence networks regulated by PhoP. A combined transcriptomic and proteomic analysis revealed that PhoP controls a variety of functions including: hypoxia response through DosR crosstalking, respiratory metabolism, secretion of the major T-cell antigen ESAT-6, stress response, synthesis of pathogenic lipids and the M. tuberculosis persistence through transcriptional regulation of the enzyme isocitrate lyase. We also demonstrate that the M. tuberculosis phoP mutant SO2 exhibits an antigenic capacity similar to that of the BCG vaccine. Finally, we provide evidence that the SO2 mutant persists better in mouse organs than BCG. Altogether, these findings indicate that PhoP orchestrates a variety of functions implicated in M. tuberculosis virulence and persistence, making phoP mutants promising vaccine candidates.
Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide  [PDF]
Andrew M. Lippa,Mark Goulian
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000788
Abstract: The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system.
Interactions of Attenuated Mycobacterium tuberculosis phoP Mutant with Human Macrophages  [PDF]
Nadia L. Ferrer,Ana B. Gomez,Olivier Neyrolles,Brigitte Gicquel,Carlos Martin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012978
Abstract: Mycobacterium tuberculosis phoP mutant SO2 derived from a clinical isolate was shown to be attenuated in mouse bone marrow-derived macrophages and in vivo mouse infection model and has demonstrated a high potential as attenuated vaccine candidate against tuberculosis.
Molecular Characterization of Transcriptional Regulation of rovA by PhoP and RovA in Yersinia pestis  [PDF]
Yiquan Zhang,He Gao,Li Wang,Xiao Xiao,Yafang Tan,Zhaobiao Guo,Dongsheng Zhou,Ruifu Yang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025484
Abstract: Yersinia pestis is the causative agent of plague. The two transcriptional regulators, PhoP and RovA, are required for the virulence of Y. pestis through the regulation of various virulence-associated loci. They are the global regulators controlling two distinct large complexes of cellular pathways.
Horizontally Acquired Glycosyltransferase Operons Drive Salmonellae Lipopolysaccharide Diversity  [PDF]
Mark R. Davies,Sarah E. Broadbent,Simon R. Harris,Nicholas R. Thomson,Marjan W. van der Woude
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003568
Abstract: The immunodominant lipopolysaccharide is a key antigenic factor for Gram-negative pathogens such as salmonellae where it plays key roles in host adaptation, virulence, immune evasion, and persistence. Variation in the lipopolysaccharide is also the major differentiating factor that is used to classify Salmonella into over 2600 serovars as part of the Kaufmann-White scheme. While lipopolysaccharide diversity is generally associated with sequence variation in the lipopolysaccharide biosynthesis operon, extraneous genetic factors such as those encoded by the glucosyltransferase (gtr) operons provide further structural heterogeneity by adding additional sugars onto the O-antigen component of the lipopolysaccharide. Here we identify and examine the O-antigen modifying glucosyltransferase genes from the genomes of Salmonella enterica and Salmonella bongori serovars. We show that Salmonella generally carries between 1 and 4 gtr operons that we have classified into 10 families on the basis of gtrC sequence with apparent O-antigen modification detected for five of these families. The gtr operons localize to bacteriophage-associated genomic regions and exhibit a dynamic evolutionary history driven by recombination and gene shuffling events leading to new gene combinations. Furthermore, evidence of Dam- and OxyR-dependent phase variation of gtr gene expression was identified within eight gtr families. Thus, as O-antigen modification generates significant intra- and inter-strain phenotypic diversity, gtr-mediated modification is fundamental in assessing Salmonella strain variability. This will inform appropriate vaccine and diagnostic approaches, in addition to contributing to our understanding of host-pathogen interactions.
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