MOLECULAR PATHOGENESIS GRAM-NEGATIVE BACTERIAL PATHOGENS AND AMR
We have several intertwined research streams:
EPEC AND EHEC PATHOGENESIS AND HOST RESPONSES
We investigate infections with enterohaemorrhagic Escherichia coli (EHEC), which causes haemorrhagic colitis and haemolytic uraemic syndrome (HUS), and enteropathogenic E. coli (EPEC), which causes paediatric diarrhoea mainly in low and middle-income countries. EPEC and EHEC employ a type III secretion system (T3SS) to inject dozens of effectors that take control of cell signaling (1,2). We study the structure and function of the effectors (for example 3,4).
Mice are inherently resistant to EPEC and EHEC infection. For this reason we extensively make use of the related mouse pathogen Citrobacter rodentium, which shares an infection strategy and effectors with EPEC and EHEC (5,6). In particular, we investigate the impact of C. rodentium infection on infected intestinal epithelial cells (IECs) in vivo using isobaric labelling proteomics, targeted metabolomics and lipidomics. We also study the impact of C. rodentium infection on the composition of faecal and mucosal associated gut microbiota.
EHEC, EPEC and C. rodentium colonise the gut mucosa via formation of attaching and effacing lesions.
Infections with Salmonella Typhi belonging to haplotype H58
Salmonella enterica serovar Typhi (S. Typhi) cause the systemic disease, typhoid fever. Its virulence depends on the activity of two T3SSs carried on Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2), which secrete a pool of over 40 effectors to subvert host cell processes to permit immune evasion, invasion, and intracellular growth. The need to better understand S. Typhi infection has been intensified by the recent spread of haplotype 58 (H58), also known as 4.3.1, that has clonally expanded worldwide to become the dominant cause of multi-drug resistant (MDR) typhoid across South and Southeast Asia and East Africa. We are aiming to understand the reasons underlying the relative success of H58 strains (7,8).
Differential SPI-1 gene expression between S. Typhimurium,
S. Typhi Ty2 and S. Typhi belonging to the H58 clade
Antimicrobial resistance and tracking commensal E. coli
We face a growing threat from the spread of antimicrobial resistance and an on-going high burden of diarrhoeal diseases, particularly in young children. To address these challenges we use mouse models to investigate the impact of infection with ETEC, the effect of antibiotic treatments on the gut physiology and the microbiota, the consequences of treating infections with antibiotic resistant pathogens, and to track commensal E. coli in vivo under various stress conditions (e.g. infection, inflammation, diet). These studies benefit significantly from our in vivo imaging capability.
3D imaging of a mouse infected with bioluminescent C. rodentium
Cover illustration created by Agnes Sågfors, who also designs and produces art for many of our published figures.
These projects are supported by a cross council grant “tackling AMR Theme 1: Understanding resistant bacteria in context of the host” and by a Royal Society International Collaboration Awards for Research Professors.
1. Garmendia, J., Frankel, G., and Crepin, V.F. Enteropathogenic and enterohemorrhagic E. coli infections: translocation, translocation, translocation. Infect. Immun. 73 (2005), 2573-2585
2. Raymond, B., Young, J.C., Pallett, M., Endres, R.G., Clements, A., and Frankel, G. Subversion of trafficking, apoptosis and innate immunity by type III secretion system effectors. Trends Microbiol. 21 (2013), 430-441
3. Young, C., Clements, A., Lang, A.E., Garnett, J.A., Munera, D., Arbeloa, A., Pearson, J., Hartland, E.L., Matthews, S.J., Mousnier, A., Barry, D.J., Way, M., Schlosser, A., Aktories, K., and Frankel, G. The E. coli effector EspJ blocks Src kinase activity via amidation and ADP-ribosylation. Nat Comm. 5 (2014), 5887
4. Pearson, J.S., Giogha, C., Ong, S.Y., Kennedy, C.L., Kelly, M., Robinson, K.S., Wong, T., Mansell, A., Riedmaier, P., Oates, C.V.L, Zaid, A., Mühle, S., Crepin, V.F., Marches, O., Ang, C.H., Williamson, N.A., O’Reilly, L.A., Bankovacki, A., Nachbur, U., Infusini, G., Webb, A.I., Silke, J., Strasser, A., Frankel, G., and Hartland, E.L. A type III effector antagonises death receptor signalling during bacterial gut infection. Nature 501 (2013), 247-251
5. Collins, J.W., Keeney, K.M., Crepin, V.F., Rathinam, V.A.K., Fitzgerald, K.A., Finlay, B.B., and Frankel, G. Citrobacter rodentium: infection, inflammation and the microbiota. Nat. Rev. Microbiol. 12 (2014), 612-623
6. Crepin, V.F., Collins, J., Habibzay, M., and Frankel, G. Citrobacter rodentium mouse model of bacterial infection. Nature Protocols 11 (2016), 1851–1876
7. Johnson, R., Byrne, A., Berger, C.N., Klemm, E., Crepin, V.F., Dougan, G., and Frankel, G. The type III secretion system effector SptP of Salmonella enterica serovar Typhi. J. Bacteriol. (2016), DOI: 10.1128/JB.00647-16.
8. Johnson, R. , Ravenhall, M,, Pickard, D., Dougan, G., Byrne, A. and Frankel, G. Comparison of Salmonella enterica Serovars Typhi and Typhimurium Reveals Typhoidal Serovar-Specific Responses to Bile. Infect. Immun. (2018) 86, 3 e00490-17
Professor Gad Frankel
Gad Frankel obtained his B.Sc. in Biology and subsequently his Ph.D in Genetics from the Hebrew University of Jerusalem. He has held a Howard Hughes Fellowship in the Department Microbiology and Immunology, Stanford University, CA, USA. Following a short stay at the Weizmann Institute in Rehovot, he was appointed a research fellow at Imperial College. In 1998 he was appointed Lecturer at Imperial College, was promoted to Reader in 2000 and to Professor in 2002. He is currently Professor of Bacterial Pathogenesis at the Department of Life Sciences and the MRC Centre for Molecular Bacteriology and Infection (CMBI) at Imperial College London.
|Dr Rachael Barry||Dr Cedric N Berger||Dr Louise E Kerry||Dr Olga Kotik|
|Research Associate||Research Fellow||Laboratory Manager||Research Technician|
|Dr Rebecca Johnson||Dr Carrie Mullineaux-Sanders||Dr David Ruano-Gallego||Dr Joshua L C Wong|
|Research Associate||Clinical Research Training Fellow|
|Ms Pippa Goddard||Ms Eve Hopkins|
|PhD Student||PhD Student||
|Ms Sabrina L Slater||Mr Qiyun Zhong||Ms Tabitha Sleap|
|PhD Student||PhD Student||MRes Student|
et 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
et al., 2017, Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo, Cell Metabolism, Vol:26, ISSN:1550-4131, Pages:738-+
et al., 2012, EspZ of Enteropathogenic and Enterohemorrhagic Escherichia coli Regulates Type III Secretion System Protein Translocation, MBIO, Vol:3, ISSN:2150-7511
et al., 2013, A type III effector antagonizes death receptor signalling during bacterial gut infection, Nature, Vol:501, ISSN:0028-0836, Pages:247-+