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Polyamines Are Required for Virulence in Salmonella enterica Serovar Typhimurium  [PDF]
Lotte Jelsbak, Line Elnif Thomsen, Inke Wallrodt, Peter Ruhdal Jensen, John Elmerdahl Olsen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036149
Abstract: Sensing and responding to environmental cues is a fundamental characteristic of bacterial physiology and virulence. Here we identify polyamines as novel environmental signals essential for virulence of Salmonella enterica serovar Typhimurium, a major intracellular pathogen and a model organism for studying typhoid fever. Central to its virulence are two major virulence loci Salmonella Pathogenicity Island 1 and 2 (SPI1 and SPI2). SPI1 promotes invasion of epithelial cells, whereas SPI2 enables S. Typhimurium to survive and proliferate within specialized compartments inside host cells. In this study, we show that an S. Typhimurium polyamine mutant is defective for invasion, intracellular survival, killing of the nematode Caenorhabditis elegans and systemic infection of the mouse model of typhoid fever. Virulence of the mutant could be restored by genetic complementation, and invasion and intracellular survival could, as well, be complemented by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection. Interestingly, intracellular survival of the polyamine mutant was significantly enhanced above the wild type level by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection, indicating that these polyamines function as an environmental signal that primes S. Typhimurium for intracellular survival. Accordingly, experiments addressed at elucidating the roles of these polyamines in infection revealed that expression of genes from both of the major virulence loci SPI1 and SPI2 responded to exogenous polyamines and was reduced in the polyamine mutant. Together our data demonstrate that putrescine and spermidine play a critical role in controlling virulence in S. Typhimurium most likely through stimulation of expression of essential virulence loci. Moreover, our data implicate these polyamines as key signals in S. Typhimurium virulence.
Oxidoreductases that Act as Conditional Virulence Suppressors in Salmonella enterica Serovar Typhimurium  [PDF]
Naeem Anwar, Xiao Hui Sem, Mikael Rhen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064948
Abstract: In Salmonella enterica serovar Typhimurium, oxidoreductases of the thioredoxin superfamily contribute to bacterial invasiveness, intracellular replication and to the virulence in BALB/c mice as well as in the soil nematode Caenorhabditis elegans. The scsABCD gene cluster, present in many but not all enteric bacteria, codes for four putative oxidoreductases of the thioredoxin superfamily. Here we have analyzed the potential role of the scs genes in oxidative stress tolerance and virulence in S. Typhimurium. An scsABCD deletion mutant showed moderate sensitization to the redox-active transition metal ion copper and increased protein carbonylation upon exposure to hydrogen peroxide. Still, the scsABCD mutant was not significantly affected for invasiveness or intracellular replication in respectively cultured epithelial or macrophage-like cells. However, we noted a significant copper chloride sensitivity of SPI1 T3SS mediated invasiveness that strongly depended on the presence of the scs genes. The scsABCD deletion mutant was not attenuated in animal infection models. In contrast, the mutant showed a moderate increase in its competitive index upon intraperitoneal challenge and enhanced invasiveness in small intestinal ileal loops of BALB/c mice. Moreover, deletion of the scsABCD genes restored the invasiveness of a trxA mutant in epithelial cells and its virulence in C. elegans. Our findings thus demonstrate that the scs gene cluster conditionally affects virulence and underscore the complex interactions between oxidoreductases of the thioredoxin superfamily in maintaining host adaptation of S. Typhimurium.
Complete Nucleotide Sequences of Virulence-Resistance Plasmids Carried by Emerging Multidrug-Resistant Salmonella enterica Serovar Typhimurium Isolated from Cattle in Hokkaido, Japan  [PDF]
Yukino Tamamura, Kiyoshi Tanaka, Masato Akiba, Toru Kanno, Shinichi Hatama, Ryoko Ishihara, Ikuo Uchida
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077644
Abstract: In the present study, we have shown that virulence-resistance plasmids from emerging multidrug-resistant isolates of Salmonella enterica serovar Typhimurium were derived from a virulence-associated plasmid, essential for systematic invasiveness of S. Typhimurium in mice (pSLT), through acquisition of a large insert containing a resistance island flanked by IS1294 elements. A blaCMY-2-carrying plasmid from a cefotaxime-resistant isolate comprised a segment of Escherichia coli plasmid pAR060302 and the replication region (IncFIB) of a virulence-resistance plasmid. These results provide insights into the evolution of drug resistance in emerging clones of S. Typhimurium.
Comparative proteomic analysis of Salmonella enterica serovar Typhimurium ppGpp-deficient mutant to identify a novel virulence protein required for intracellular survival in macrophages
Takeshi Haneda, Mariko Sugimoto, Yukie Yoshida-Ohta, Yoshio Kodera, Masamichi Oh-Ishi, Tadakazu Maeda, Satomi Shimizu-Izumi, Tsuyoshi Miki, Yoshinori Kumagai, Hirofumi Danbara, Nobuhiko Okada
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-324
Abstract: Of the 366 examined spots, 269 proteins were successfully identified. The comparative analysis of the wild-type and ppGpp0 mutant strains revealed 55 proteins, the expression patterns of which were affected by ppGpp. Using a mouse infection model, we further identified a novel virulence-associated factor, STM3169, from the ppGpp-regulated and Salmonella-specific proteins. In addition, Salmonella strains carrying mutations in the gene encoding STM3169 showed growth defects and impaired growth within macrophage-like RAW264.7 cells. Furthermore, we found that expression of stm3169 was controlled by ppGpp and SsrB, a response regulator of the two-component system located on Salmonella pathogenicity island 2.A proteomic approach using a 2-DE reference map can prove a powerful tool for analyzing virulence factors and the regulatory network involved in Salmonella pathogenesis. Our results also provide evidence of a global response mediated by ppGpp in S. enterica.The facultative intracellular bacterium Salmonella enterica causes a broad spectrum of diseases, such as gastroenteritis and bacteremia, which are typically acquired by oral ingestion of contaminated food or water. S. enterica serovar Typhimurium (S. Typhimurium) causes enterocolitis in humans and a typhoid-like systemic infection in mice.Several virulence genes associated with Salmonella pathogenicity islands (SPIs) and the virulence plasmid have been characterized in S. Typhimurium. Two type III secretion systems (T3SS) encoded by SPI-1 and SPI-2 play central roles in Salmonella pathogenesis. SPI-1 is essential for the invasion of host cells and the induction of apoptosis in infected macrophages [1,2]. SPI-2 T3SS primarily confers survival and replication on macrophages and is required for systemic infection in the mouse infection model [3,4]. Expression of SPI-2 genes is induced within a modified phagosome, called the Salmonella-containing vacuole (SCV), in infected macrophages [5]. Induction of SPI-2 genes dep
Effects of indole on drug resistance and virulence of Salmonella enterica serovar Typhimurium revealed by genome-wide analyses
Eiji Nikaido, Etienne Giraud, Sylvie Baucheron, Suguru Yamasaki, Agnès Wiedemann, Kousuke Okamoto, Tatsuya Takagi, Akihito Yamaguchi, Axel Cloeckaert, Kunihiko Nishino
Gut Pathogens , 2012, DOI: 10.1186/1757-4749-4-5
Abstract: To understand the complete picture of genes regulated by indole, we performed DNA microarray analysis of genes in the S. enterica serovar Typhimurium strain ATCC 14028s affected by indole. Predicted Salmonella phenotypes affected by indole based on the microarray data were also examined in this study. Indole induced expression of genes related to efflux-mediated multidrug resistance, including ramA and acrAB, and repressed those related to host cell invasion encoded in the Salmonella pathogenicity island 1, and flagella production. Reduction of invasive activity and motility of Salmonella by indole was also observed phenotypically.Our results suggest that indole is an important signaling molecule for inter-species communication to control drug resistance and virulence of S. enterica.Bacteria communicate using small molecules by a process termed quorum sensing. Accumulation of quorum-sensing signals in growth medium indicates cell density. The use of chemical signals for bacterial communication is a widespread phenomenon [1-5]. In Gram-negative bacteria, these signals could be N-acyl derivatives of homoserine lactone, cyclic dipeptides, and quinolones [6-12]. These signals regulate various functions such as bioluminescence, differentiation, virulence, DNA transfer, and biofilm maturation [13-22].The intestinal tract is colonized by approximately 1012 commensal bacteria including those belonging to the genus Escherichia[23-25]. Among Enterobacteriaceae, indole is produced by E. coli and certain Proteeae such as Proteus vulgarisProvidencia spp., and Morganella spp. [26]. Indole production is commonly used for Escherichia coli identification [26]. Indole is generated from tryptophan by the enzyme tryptophanase, encoded by tnaA[27]. Extracellular indole is found at high concentrations (over 600 μM) when E. coli is grown in enriched medium [28]. Furthermore, indole has also been found in human feces at comparable concentrations (~250–1100 μM) [29,30]. Recent studies have
Complex c-di-GMP Signaling Networks Mediate Transition between Virulence Properties and Biofilm Formation in Salmonella enterica Serovar Typhimurium  [PDF]
Irfan Ahmad, Agaristi Lamprokostopoulou, Soazig Le Guyon, Elena Streck, Melanie Barthel, Verena Peters, Wolf-Dieter Hardt, Ute R?mling
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028351
Abstract: Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature.
Diversity of Plasmids Encoding Virulence and Resistance Functions in Salmonella enterica subsp. enterica Serovar Typhimurium Monophasic Variant 4,[5],12:i:- Strains Circulating in Europe  [PDF]
Patricia García, Katie L. Hopkins, Vanesa García, Janine Beutlich, M. Carmen Mendoza, John Threlfall, Dik Mevius, Reiner Helmuth, M. Rosario Rodicio, Beatriz Guerra, on behalf of the Med-Vet-Net WP21 Project Group
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089635
Abstract: Plasmids encoding resistance and virulence properties in multidrug resistant (MDR) Salmonella enterica (S.) serovar Typhimurium monophasic variant 4,[5],12:i:- isolates recovered from pigs and humans (2006-2008) in Europe were characterised. The isolates were selected based on the detection by PCR-amplification of S. Typhimurium virulence plasmid pSLT genes and were analysed by multi-locus sequence typing (MLST). The resistance genes present in the isolates and the association of these genes with integrons, transposons and insertion sequences were characterised by PCR-sequencing, and their plasmid location was determined by alkaline lysis and by S1-nuclease pulsed-field gel electrophoresis (PFGE) Southern-blot hybridisation. Plasmids were further analysed by replicon typing, plasmid MLST and conjugation experiments. The 10 S. 4,[5],12,i:- selected isolates belonged to ST19. Each isolate carried a large plasmid in which MDR with pSLT-associated virulence genes were located. After analysis, eight different plasmids of three incompatibility groups (IncA/C, IncR and IncF) were detected. Two IncA/C plasmids represented novel variants within the plasmid family of the S. 4,[5],12:i:- Spanish clone, and carried an empty class 1 integron with a conventional qacEΔ1-sul1 3′ conserved segment or an In-sul3 type III with estX-psp-aadA2-cmlA1-aadA1-qacH variable region linked to tnpA440-sul3, part of Tn2, Tn21 and Tn1721 transposons, and ISCR2. Four newly described IncR plasmids contained the resistance genes within In-sul3 type I (dfrA12-orfF-aadA2-cmlA1-aadA1-qacH/tnpA440-sul3) and part of Tn10 [tet(B)]. Two pSLT-derivatives with FIIs-ST1+FIB-ST17 replicons carried cmlA1-[aadA1-aadA2]-sul3-dfrA12 and blaTEM-1 genes linked to an In-sul3 type I integron and to Tn2, respectively. In conclusion, three emerging European clones of S. 4,[5],12:i:- harboured MDR plasmids encoding additional virulence functions that could contribute significantly to their evolutionary success.
YqiC of Salmonella enterica serovar Typhimurium is a membrane fusogenic protein required for mice colonization
Mariela C Carrica, Patricio O Craig, Víctor A García-Angulo, Andes Aguirre, Eleonora García-Véscovi, Fernando A Goldbaum, Silvio L Cravero
BMC Microbiology , 2011, DOI: 10.1186/1471-2180-11-95
Abstract: In this work we present structural information as well as insights into the in vivo function of YqiC, a 99-residue protein of S. Typhimurium, which belongs to the cluster of the orthologous group 2960 (COG2960). We found that YqiC shares biophysical and biochemical properties with Brucella abortus BMFP, the only previously characterized member of this group, such as a high alpha helix content, a coiled-coil domain involved in trimerization and a membrane fusogenic activity in vitro. In addition, we demonstrated that YqiC localizes at cytoplasmic and membrane subcellular fractions, that a S. Typhimurium yqiC deficient strain had a severe attenuation in virulence in the murine model when inoculated both orally and intraperitoneally, and was impaired to replicate at physiological and high temperatures in vitro, although it was still able to invade and replicate inside epithelial and macrophages cell lines.This work firstly demonstrates the importance of a COG2960 member for pathogen-host interaction, and suggests a common function conserved among members of this group.Salmonella enterica is an intracellular facultative anaerobe Gram-negative that infects a variety of hosts, which include mammals, avians and reptiles. In human beings, S. enterica causes over 33 million cases of disease worldwide annually, which may vary from gastroenteritis and diarrhea to severe life-threatening systemic disease (typhoid fever) [1]. The outcome of the disease depends on both the serovar of Samonella and the host susceptibility. Salmonella enterica serovar Typhimurium (S. Typhimurium), can infect humans and animals, but causes different syndromes in each host. In humans, Salmonella produces enterocolitis, but in mice it causes a systemic illness that resembles human typhoid fever. Because of this, S. Typhimurium is widely used as a model organism to study the host-pathogen interactions that contribute to the onset of the systemic disease [2,3].The pathogenic strategy of S. Typhimurium i
The PagN protein of Salmonella enterica serovar Typhimurium is an adhesin and invasin
Matthew A Lambert, Stephen GJ Smith
BMC Microbiology , 2008, DOI: 10.1186/1471-2180-8-142
Abstract: Here we show that the outer membrane located PagN protein mediates agglutination of red blood cells and that this can be masked by LPS. When expressed in Escherichia coli the PagN protein supports adhesion to and invasion of mammalian cells in a manner that is dependent on cytoskeletal rearrangements. S. enterica sv Typhimurium pagN mutants display a reduction in adhesion to and invasion of epithelial cells. Finally, we demonstrate that over-expression of PagN in a SPI-1 mutant can partially compensate for the lack of a functional invasasome.PagN is an outer membrane protein that may contribute to the virulence of S. Typhimurium. This protein is a haemagglutinin and contributes to the adherence to mammalian cells. In addition, PagN can mediate high-level invasion of CHO-K1 cells. Previously,pagN mutants have been shown to be less competitive in vivo and thus this may be due to their lessened ability to interact with mammalian cells. Finally PagN can be added to an ever-growing repertoire of factors that contribute to the pathogenesis of Salmonella.Salmonella enterica serovar Typhimurium infects a wide range of animal hosts and typically causes a self-limiting gastroenteritis [1]. Initial symptoms include nausea and vomiting, which are followed by abdominal pain and diarrhoea. S. Typhimurium adheres to intestinal epithelial cells using a myriad of fimbriae including Type 1 fimbriae [2]. Outer membrane proteins such as the plasmid-encoded Rck [3-5] and the OmpD [6] protein also mediate attachment to epithelial cells. Deletion of either rck or ompD results in decreased invasion of intestinal epithelial cells [5,6]. Upon adhesion the subsequent uptake of Salmonella into mammalian cells is a complex process that is coordinated by a series of proteins that are encoded within the SPI-1 and SPI-5 pathogenicity islands [1]. The SPI-1 locus encodes a type three secretion system (T3SS), also known as an invasasome, that delivers effector protein including the Salmonella outer
Divergent Roles of Salmonella Pathogenicity Island 2 and Metabolic Traits during Interaction of S. enterica Serovar Typhimurium with Host Cells  [PDF]
Stefanie U. H?lzer, Michael Hensel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033220
Abstract: The molecular mechanisms of virulence of the gastrointestinal pathogen Salmonella enterica are commonly studied using cell culture models of infection. In this work, we performed a direct comparison of the interaction of S. enterica serovar Typhimurium (S. Typhimurium) with the non-polarized epithelial cell line HeLa, the polarized cell lines CaCo2, T84 and MDCK, and macrophage-like RAW264.7 cells. The ability of S. Typhimurium wild-type and previously characterized auxotrophic mutant strains to enter host cells, survive and proliferate within mammalian cells and deploy the Salmonella Pathogenicity Island 2-encoded type III secretion system (SPI2-T3SS) was quantified. We found that the entry of S. Typhimurium into polarized cells was much more efficient than entry into non-polarized cells or phagocytic uptake. While SPI2-T3SS dependent intracellular proliferation was observed in HeLa and RAW cells, the intracellular replication in polarized cells was highly restricted and not affected by defective SPI2-T3SS. The contribution of aromatic amino acid metabolism and purine biosynthesis to intracellular proliferation was distinct in the various cell lines investigated. These observations indicate that the virulence phenotypes of S. Typhimurium are significantly affected by the cell culture model applied.
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