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  • Journal article
    Pfanzelter J, Mostowy S, Way M, 2018,

    Septins suppress the release of vaccinia virus from infected cells.

    , J Cell Biol, Vol: 217, Pages: 2911-2929

    Septins are conserved components of the cytoskeleton that play important roles in many fundamental cellular processes including division, migration, and membrane trafficking. Septins can also inhibit bacterial infection by forming cage-like structures around pathogens such as Shigella We found that septins are recruited to vaccinia virus immediately after its fusion with the plasma membrane during viral egress. RNA interference-mediated depletion of septins increases virus release and cell-to-cell spread, as well as actin tail formation. Live cell imaging reveals that septins are displaced from the virus when it induces actin polymerization. Septin loss, however, depends on the recruitment of the SH2/SH3 adaptor Nck, but not the activity of the Arp2/3 complex. Moreover, it is the recruitment of dynamin by the third Nck SH3 domain that displaces septins from the virus in a formin-dependent fashion. Our study demonstrates that septins suppress vaccinia release by "entrapping" the virus at the plasma membrane. This antiviral effect is overcome by dynamin together with formin-mediated actin polymerization.

  • Journal article
    Bernal P, Llamas MA, Filloux A, 2018,

    Type VI secretion systems in plant-associated bacteria

    , Environmental Microbiology, Vol: 20, Pages: 1-15, ISSN: 1462-2912

    The type VI secretion system (T6SS) is a bacterial nanomachine used to inject effectors into prokaryotic or eukaryotic cells and is thus involved in both host manipulation and interbacterial competition. The T6SS is widespread among Gram‐negative bacteria, mostly within the Proteobacterium Phylum. This secretion system is commonly found in commensal and pathogenic plant‐associated bacteria. Phylogenetic analysis of phytobacterial T6SS clusters shows that they are distributed in the five main clades previously described (group 1–5). The even distribution of the system among commensal and pathogenic phytobacteria suggests that the T6SS provides fitness and colonization advantages in planta and that the role of the T6SS is not restricted to virulence. This manuscript reviews the phylogeny and biological roles of the T6SS in plant‐associated bacteria, highlighting a remarkable diversity both in terms of mechanism and function.

  • Journal article
    Mullineaux-Sanders C, Colins JW, Ruano-Gallego D, Levy M, Pevsner-Fischer M, Glegola-Madejska IT, Sagfors AM, Wong JLC, Elinav E, Crepin VF, Frankel GMet al., 2017,

    Citrobacter rodentium relies on commensals for colonization of the colonic mucosa

    , Cell Reports, Vol: 21, Pages: 3381-3389, ISSN: 2211-1247

    We investigated the role of commensals at the peak of infection with the colonic mouse pathogen Citrobacter rodentium. Bioluminescent and kanamycin (Kan)-resistant C. rodentium persisted avirulently in the cecal lumen of mice continuously treated with Kan. A single Kan treatment was sufficient to displace C. rodentium from the colonic mucosa, a phenomenon not observed following treatment with vancomycin (Van) or metronidazole (Met). Kan, Van, and Met induce distinct dysbiosis, suggesting C. rodentium relies on specific commensals for colonic colonization. Expression of the master virulence regulator ler is induced in germ-free mice, yet C. rodentium is only seen in the cecal lumen. Moreover, in conventional mice, a single Kan treatment was sufficient to displace C. rodentium constitutively expressing Ler from the colonic mucosa. These results show that expression of virulence genes is not sufficient for colonization of the colonic mucosa and that commensals are essential for a physiological infection course.

  • Journal article
    Johnson R, Ravenhall M, Pickard D, Dougan G, Byrne A, Frankel GMet al., 2017,

    Comparison of Salmonella enterica serovars Typhi and Typhimurium reveals typhoidal-specific responses to bile

    , Infection and Immunity, Vol: 86, ISSN: 0019-9567

    Salmonella enterica serovars Typhi and Typhimurium cause typhoid fever and gastroenteritis respectively. A unique feature of typhoid infection is asymptomatic carriage within the gallbladder, which is linked with S. Typhi transmission. Despite this, S. Typhi responses to bile have been poorly studied. RNA-Seq of S. Typhi Ty2 and a clinical S. Typhi isolate belonging to the globally dominant H58 lineage (129-0238), as well as S. Typhimurium 14028, revealed that 249, 389 and 453 genes respectively were differentially expressed in the presence of 3% bile compared to control cultures lacking bile. fad genes, the actP-acs operon, and putative sialic acid uptake and metabolism genes (t1787-t1790) were upregulated in all strains following bile exposure, which may represent adaptation to the small intestine environment. Genes within the Salmonella pathogenicity island 1 (SPI-1), encoding a type IIII secretion system (T3SS), and motility genes were significantly upregulated in both S. Typhi strains in bile, but downregulated in S. Typhimurium. Western blots of the SPI-1 proteins SipC, SipD, SopB and SopE validated the gene expression data. Consistent with this, bile significantly increased S. Typhi HeLa cell invasion whilst S. Typhimurium invasion was significantly repressed. Protein stability assays demonstrated that in S. Typhi the half-life of HilD, the dominant regulator of SPI-1, is three times longer in the presence of bile; this increase in stability was independent of the acetyltransferase Pat. Overall, we found that S. Typhi exhibits a specific response to bile, especially with regards to virulence gene expression, which could impact pathogenesis and transmission.

  • Journal article
    Portaliou AG, Tsolis KC, Loos MS, Balabanidou V, Rayo J, Tsirigotaki A, Crepin VF, Frankel G, Kalodimos CG, Karamanou S, Economou Aet al., 2017,

    Hierarchical protein targeting and secretion is controlled by an affinity switch in the type III secretion system of enteropathogenic Escherichia coli

    , EMBO JOURNAL, Vol: 36, Pages: 3517-3531, ISSN: 0261-4189
  • Journal article
    Cepeda-Molero M, Berger CN, Walsham ADS, Ellis SJ, Wemyss-Holden S, Schueller S, Frankel G, Angel Fernandez Let al., 2017,

    Attaching and effacing (A/E) lesion formation by enteropathogenic E. coli on human intestinal mucosa is dependent on non-LEE effectors

    , PLoS Pathogens, Vol: 13, ISSN: 1553-7366

    Enteropathogenic E. coli (EPEC) is a human pathogen that causes acute and chronic pediatric diarrhea. The hallmark of EPEC infection is the formation of attaching and effacing (A/E) lesions in the intestinal epithelium. Formation of A/E lesions is mediated by genes located on the pathogenicity island locus of enterocyte effacement (LEE), which encode the adhesin intimin, a type III secretion system (T3SS) and six effectors, including the essential translocated intimin receptor (Tir). Seventeen additional effectors are encoded by genes located outside the LEE, in insertion elements and prophages. Here, using a stepwise approach, we generated an EPEC mutant lacking the entire effector genes (EPEC0) and intermediate mutants. We show that EPEC0 contains a functional T3SS. An EPEC mutant expressing intimin but lacking all the LEE effectors but Tir (EPEC1) was able to trigger robust actin polymerization in HeLa cells and mucin-producing intestinal LS174T cells. However, EPEC1 was unable to form A/E lesions on human intestinal in vitro organ cultures (IVOC). Screening the intermediate mutants for genes involved in A/E lesion formation on IVOC revealed that strains lacking non-LEE effector/s have a marginal ability to form A/E lesions. Furthermore, we found that Efa1/LifA proteins are important for A/E lesion formation efficiency in EPEC strains lacking multiple effectors. Taken together, these results demonstrate the intricate relationships between T3SS effectors and the essential role non-LEE effectors play in A/E lesion formation on mucosal surfaces.

  • Journal article
    Berger C, Crepin V, Roumeliotis TI, Wright JC, Carson D, Pevsner-Fischer M, Furniss RCD, Dougan G, Bachash M, Yu L, Clements A, Collins JW, Elinav E, larrouy-maumus G, Choudhary JS, Frankel GMet al., 2017,

    Citrobacter rodentium subverts ATP flux 1 and cholesterol homeostasis in 2 intestinal epithelial cell in vivo

    , Cell Metabolism, Vol: 26, Pages: 738-752.e6, ISSN: 1550-4131

    The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem.

  • Journal article
    Wen KY, Cameron L, Chappell J, Jensen K, Bell DJ, Kelwick R, Kopniczky M, Davies JC, Filloux A, Freemont PSet al., 2017,

    A Cell-Free Biosensor for Detecting Quorum Sensing Molecules in P. aeruginosa-Infected Respiratory Samples.

    , ACS Synthetic Biology, Vol: 6, Pages: 2293-2301, ISSN: 2161-5063

    Synthetic biology designed cell-free biosensors are a promising new tool for the detection of clinically relevant biomarkers in infectious diseases. Here, we report that a modular DNA-encoded biosensor in cell-free protein expression systems can be used to measure a bacterial biomarker of Pseudomonas aeruginosa infection from human sputum samples. By optimizing the cell-free system and sample extraction, we demonstrate that the quorum sensing molecule 3-oxo-C12-HSL in sputum samples from cystic fibrosis lungs can be quantitatively measured at nanomolar levels using our cell-free biosensor system, and is comparable to LC-MS measurements of the same samples. This study further illustrates the potential of modular cell-free biosensors as rapid, low-cost detection assays that can inform clinical practice.

  • Journal article
    McCarthy RR, Valentini M, Filloux A, 2017,

    Contribution of Cyclic di-GMP in the Control of Type III and Type VI Secretion in Pseudomonas aeruginosa.

    , Methods Mol Biol, Vol: 1657, Pages: 213-224

    Bacteria produce toxins to enhance their competitiveness in the colonization of an environment as well as during an infection. The delivery of toxins into target cells is mediated by several types of secretion systems, among them our focus is Type III and Type VI Secretion Systems (T3SS and T6SS, respectively). A thorough methodology is provided detailing how to identify if cyclic di-GMP signaling plays a role in the P. aeruginosa toxin delivery mediated by T3SS or T6SS. This includes in vitro preparation of the samples for Western blot analysis aiming at detecting possible c-di-GMP-dependent T3SS/T6SS switch, as well as in vivo analysis using the model organism Galleria mellonella to demonstrate the ecological and pathogenic consequence of the switch between these two secretion systems.

  • Journal article
    Karampatzakis A, Song CZ, Allsopp LP, Filloux A, Rice SA, Cohen Y, Wohland T, Török Pet al., 2017,

    Probing the internal micromechanical properties of Pseudomonas aeruginosa biofilms by Brillouin imaging.

    , NPJ Biofilms Microbiomes, Vol: 3, ISSN: 2055-5008

    Biofilms are organised aggregates of bacteria that adhere to each other or surfaces. The matrix of extracellular polymeric substances that holds the cells together provides the mechanical stability of the biofilm. In this study, we have applied Brillouin microscopy, a technique that is capable of measuring mechanical properties of specimens on a micrometre scale based on the shift in frequency of light incident upon a sample due to thermal fluctuations, to investigate the micromechanical properties of an active, live Pseudomonas aeruginosa biofilm. Using this non-contact and label-free technique, we have extracted information about the internal stiffness of biofilms under continuous flow. No correlation with colony size was found when comparing the averages of Brillouin shifts of two-dimensional cross-sections of randomly selected colonies. However, when focusing on single colonies, we observed two distinct spatial patterns: in smaller colonies, stiffness increased towards their interior, indicating a more compact structure of the centre of the colony, whereas, larger (over 45 μm) colonies were found to have less stiff interiors.

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