Imperial College London

ProfessorGadFrankel

Faculty of Natural SciencesDepartment of Life Sciences

Professor of Molecular Pathogenesis
 
 
 
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Contact

 

+44 (0)20 7594 5253g.frankel

 
 
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Location

 

1.46Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

222 results found

Ale A, Crepin VF, Collins JW, Constantinou N, Habibzay M, Babtie AC, Frankel G, Stumpf MPHet al., 2017, Model of Host-Pathogen Interaction Dynamics Links In Vivo Optical Imaging and Immune Responses, INFECTION AND IMMUNITY, Vol: 85, ISSN: 0019-9567

JOURNAL ARTICLE

Berger CN, Crepin VF, 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 GJ, Choudhary JS, Frankel Get al., 2017, Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo., Cell Metab

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

Johnson R, Byrne A, Berger CN, Klemm E, Crepin VF, Dougan G, Frankel Get al., 2017, The Type III Secretion System Effector SptP of Salmonella enterica Serovar Typhi, JOURNAL OF BACTERIOLOGY, Vol: 199, ISSN: 0021-9193

JOURNAL ARTICLE

Johnson R, Byrne A, Berger CN, Klemm E, Crepin VF, Dougan G, Frankel Get al., 2017, The Type III Secretion System Effector SptP of Salmonella enterica Serovar Typhi, JOURNAL OF BACTERIOLOGY, Vol: 199, ISSN: 0021-9193

JOURNAL ARTICLE

Pallett MA, Crepin VF, Serafini N, Habibzay M, Kotik O, Sanchez-Garrido J, Di Santo JP, Shenoy AR, Berger CN, Frankel Get al., 2017, Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells, MUCOSAL IMMUNOLOGY, Vol: 10, Pages: 602-612, ISSN: 1933-0219

JOURNAL ARTICLE

Pearson JS, Giogha C, Muhlen S, Nachbur U, Pham CLL, Zhang Y, Hildebrand JM, Oates CV, Lung TWF, Ingle D, Dagley LF, Bankovacki A, Petrie EJ, Schroeder GN, Crepin VF, Frankel G, Masters SL, Vince J, Murphy JM, Sunde M, Webb AI, Silke J, Hartland ELet al., 2017, EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation, NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276

JOURNAL ARTICLE

Pearson JS, Giogha C, Muhlen S, Nachbur U, Pham CLL, Zhang Y, Hildebrand JM, Oates CV, Lung TWF, Ingle D, Dagley LF, Bankovacki A, Petrie EJ, Schroeder GN, Crepin VF, Frankel G, Masters SL, Vince J, Murphy JM, Sunde M, Webb AI, Silke J, Hartland ELet al., 2017, EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation (vol 2, 16258, 2017), NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276

JOURNAL ARTICLE

Sandu P, Crepin VF, Drechsler H, McAinsh AD, Frankel G, Berger CNet al., 2017, The Enterohemorrhagic Escherichia coli Effector EspW Triggers Actin Remodeling in a Rac1-Dependent Manner., Infect Immun, Vol: 85

Enterohemorrhagic Escherichia coli (EHEC) is a diarrheagenic pathogen that colonizes the gut mucosa and induces attaching-and-effacing lesions. EHEC employs a type III secretion system (T3SS) to translocate 50 effector proteins that hijack and manipulate host cell signaling pathways, which allow bacterial colonization and subversion of immune responses and disease progression. The aim of this study was to characterize the T3SS effector EspW. We found espW in the sequenced O157:H7 and non-O157 EHEC strains as well as in Shigella boydii Furthermore, a truncated version of EspW, containing the first 206 residues, is present in EPEC strains belonging to serotype O55:H7. Screening a collection of clinical EPEC isolates revealed that espW is present in 52% of the tested strains. We report that EspW modulates actin dynamics in a Rac1-dependent manner. Ectopic expression of EspW results in formation of unique membrane protrusions. Infection of Swiss cells with an EHEC espW deletion mutant induces a cell shrinkage phenotype that could be rescued by Rac1 activation via expression of the bacterial guanine nucleotide exchange factor, EspT. Furthermore, using a yeast two-hybrid screen, we identified the motor protein Kif15 as a potential interacting partner of EspW. Kif15 and EspW colocalized in cotransfected cells, while ectopically expressed Kif15 localized to the actin pedestals following EHEC infection. The data suggest that Kif15 recruits EspW to the site of bacterial attachment, which in turn activates Rac1, resulting in modifications of the actin cytoskeleton that are essential to maintain cell shape during infection.

JOURNAL ARTICLE

Witcomb LA, Czupryna J, Francis KP, Frankel G, Taylor PWet al., 2017, Non-invasive three-dimensional imaging of Escherichia coli K1 infection using diffuse light imaging tomography combined with micro-computed tomography, METHODS, Vol: 127, Pages: 62-68, ISSN: 1046-2023

JOURNAL ARTICLE

Crepin VF, Collins JW, Habibzay M, Frankel Get al., 2016, Citrobacter rodentium mouse model of bacterial infection., Nat Protoc, Vol: 11, Pages: 1851-1876

Infection of mice with Citrobacter rodentium is a robust model to study bacterial pathogenesis, mucosal immunology, the health benefits of probiotics and the role of the microbiota during infection. C. rodentium was first isolated by Barthold from an outbreak of mouse diarrhea in Yale University in 1972 and was 'rediscovered' by Falkow and Schauer in 1993. Since then the use of the model has proliferated, and it is now the gold standard for studying virulence of the closely related human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Here we provide a detailed protocol for various applications of the model, including bacterial growth, site-directed mutagenesis, mouse inoculation (from cultured cells and after cohabitation), monitoring of bacterial colonization, tissue extraction and analysis, immune responses, probiotic treatment and microbiota analysis. The main protocol, from mouse infection to clearance and analysis of tissues and host responses, takes ∼5 weeks to complete.

JOURNAL ARTICLE

Furniss RCD, Slater S, Frankel G, Clements Aet al., 2016, Enterohaemorrhagic E. coli modulates an ARF6:Rab35 signaling axis to prevent recycling endosome maturation during infection, JOURNAL OF MOLECULAR BIOLOGY, Vol: 428, Pages: 3399-3407, ISSN: 0022-2836

JOURNAL ARTICLE

Pollard DJ, Young JC, Covarelli V, Herrera-Leon S, Connor TR, Fookes M, Walker D, Echeita A, Thomson NR, Berger CN, Frankel Get al., 2016, The Type III Secretion System Effector SeoC of Salmonella enterica subsp salamae and S. enterica subsp arizonae ADP-Ribosylates Src and Inhibits Opsonophagocytosis, INFECTION AND IMMUNITY, Vol: 84, Pages: 3618-3628, ISSN: 0019-9567

JOURNAL ARTICLE

So EC, Schroeder GN, Carson D, Mattheis C, Mousnier A, Broncel M, Tate EW, Frankel Get al., 2016, The Rab-binding Profiles of Bacterial Virulence Factors during Infection, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 291, Pages: 5832-5843, ISSN: 0021-9258

JOURNAL ARTICLE

Crepin VF, Habibzay M, Glegola-Madejska I, Guenot M, Collins JW, Frankel Get al., 2015, Tir Triggers Expression of CXCL1 in Enterocytes and Neutrophil Recruitment during Citrobacter rodentium Infection, INFECTION AND IMMUNITY, Vol: 83, Pages: 3342-3354, ISSN: 0019-9567

JOURNAL ARTICLE

Hunter PJ, Shaw RK, Berger CN, Frankel G, Pink D, Hand Pet al., 2015, Older leaves of lettuce (Lactuca spp.) support higher levels of Salmonella enterica ser. Senftenberg attachment and show greater variation between plant accessions than do younger leaves, FEMS MICROBIOLOGY LETTERS, Vol: 362, ISSN: 0378-1097

JOURNAL ARTICLE

Messens W, Bolton D, Frankel G, Liebana E, McLauchlin J, Morabito S, Oswald E, Threlfall EJet al., 2015, Defining pathogenic verocytotoxin-producing Escherichia coli (VTEC) from cases of human infection in the European Union, 2007-2010, EPIDEMIOLOGY AND INFECTION, Vol: 143, Pages: 1652-1661, ISSN: 0950-2688

JOURNAL ARTICLE

Schreiber F, Kay S, Frankel G, Clare S, Goulding D, van de Vosse E, van Dissel JT, Strugnell R, Thwaites G, Kingsley RA, Dougan G, Baker Set al., 2015, The Hd, Hj, and Hz66 flagella variants of Salmonella enterica serovar Typhi modify host responses and cellular interactions, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322

JOURNAL ARTICLE

Schroeder GN, Aurass P, Oates CV, Tate EW, Hartland EL, Flieger A, Frankel Get al., 2015, Legionella pneumophila Effector LpdA Is a Palmitoylated Phospholipase D Virulence Factor, INFECTION AND IMMUNITY, Vol: 83, Pages: 3989-4002, ISSN: 0019-9567

JOURNAL ARTICLE

So EC, Mattheis C, Tate EW, Frankel G, Schroeder GNet al., 2015, Creating a customized intracellular niche: subversion of host cell signaling by Legionella type IV secretion system effectors, CANADIAN JOURNAL OF MICROBIOLOGY, Vol: 61, Pages: 617-635, ISSN: 0008-4166

JOURNAL ARTICLE

Witcomb LA, Collins JW, McCarthy AJ, Frankel G, Taylor PWet al., 2015, Bioluminescent Imaging Reveals Novel Patterns of Colonization and Invasion in Systemic Escherichia coli K1 Experimental Infection in the Neonatal Rat, INFECTION AND IMMUNITY, Vol: 83, Pages: 4528-4540, ISSN: 0019-9567

JOURNAL ARTICLE

Clements A, Stoneham CA, Furniss RCD, Frankel Get al., 2014, Enterohaemorrhagic Escherichia coli inhibits recycling endosome function and trafficking of surface receptors, CELLULAR MICROBIOLOGY, Vol: 16, Pages: 1693-1705, ISSN: 1462-5814

JOURNAL ARTICLE

Collins JW, Chervaux C, Raymond B, Derrien M, Brazeilles R, Kosta A, Chambaud I, Crepin VF, Frankel Get al., 2014, Fermented Dairy Products Modulate Citrobacter rodentium-Induced Colonic Hyperplasia, JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1029-1041, ISSN: 0022-1899

JOURNAL ARTICLE

Collins JW, Keeney KM, Crepin VE, Rathinam VAK, Fitzgerald KA, Finlay BB, Frankel Get al., 2014, Citrobacter rodentium: infection, inflammation and the microbiota, NATURE REVIEWS MICROBIOLOGY, Vol: 12, Pages: 612-623, ISSN: 1740-1526

JOURNAL ARTICLE

Mousnier A, Schroeder GN, Stoneham CA, So EC, Garnett JA, Yu L, Matthews SJ, Choudhary JS, Hartland EL, Frankel Get al., 2014, A New Method To Determine In Vivo Interactomes Reveals Binding of the Legionella pneumophila Effector PieE to Multiple Rab GTPases, MBIO, Vol: 5, ISSN: 2150-7511

JOURNAL ARTICLE

Pallett MA, Berger CN, Pearson JS, Hartland EL, Frankel Get al., 2014, The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-kappa B Early during Infection, INFECTION AND IMMUNITY, Vol: 82, Pages: 4878-4888, ISSN: 0019-9567

JOURNAL ARTICLE

Satoh-Takayama N, Serafini N, Verrier T, Rekiki A, Renauld J-C, Frankel G, Di Santo JPet al., 2014, The Chemokine Receptor CXCR6 Controls the Functional Topography of Interleukin-22 Producing Intestinal Innate Lymphoid Cells, IMMUNITY, Vol: 41, Pages: 776-788, ISSN: 1074-7613

JOURNAL ARTICLE

Song-Zhao GX, Srinivasan N, Pott J, Baban D, Frankel G, Maloy KJet al., 2014, Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen, MUCOSAL IMMUNOLOGY, Vol: 7, Pages: 763-774, ISSN: 1933-0219

JOURNAL ARTICLE

Stevens MP, Frankel GM, 2014, The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic Escherichia coli., Microbiol Spectr, Vol: 2

A subset of Shiga toxin-producing Escherichia coli strains, termed enterohemorrhagic E. coli (EHEC), is defined in part by the ability to produce attaching and effacing (A/E) lesions on intestinal epithelia. Such lesions are characterized by intimate bacterial attachment to the apical surface of enterocytes, cytoskeletal rearrangements beneath adherent bacteria, and destruction of proximal microvilli. A/E lesion formation requires the locus of enterocyte effacement (LEE), which encodes a Type III secretion system that injects bacterial proteins into host cells. The translocated proteins, termed effectors, subvert a plethora of cellular pathways to the benefit of the pathogen, for example, by recruiting cytoskeletal proteins, disrupting epithelial barrier integrity, and interfering with the induction of inflammation, phagocytosis, and apoptosis. The LEE and selected effectors play pivotal roles in intestinal persistence and virulence of EHEC, and it is becoming clear that effectors may act in redundant, synergistic, and antagonistic ways during infection. Vaccines that target the function of the Type III secretion system limit colonization of reservoir hosts by EHEC and may thus aid control of zoonotic infections. Here we review the features and functions of the LEE-encoded Type III secretion system and associated effectors of E. coli O157:H7 and other Shiga toxin-producing E. coli strains.

JOURNAL ARTICLE

Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang J-P, Brown EM, Frankel G, Levy M, Katz MN, Philbrick WM, Elinav E, Finlay BB, Flavell RAet al., 2014, NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus Secretion, CELL, Vol: 156, Pages: 1045-1059, ISSN: 0092-8674

JOURNAL ARTICLE

Young JC, Clements A, Lang AE, Garnett JA, Munera D, Arbeloa A, Pearson J, Hartland EL, Matthews SJ, Mousnier A, Barry DJ, Way M, Schlosser A, Aktories K, Frankel Get al., 2014, The Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723

JOURNAL ARTICLE

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