Prof Ian RobertsBSc, PhD

Professor of Microbiology

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Regulation of intestinal immune responses to commensal bacteria by innate lymphoid cells

Commensal bacteria present in the gastrointestinal tract provide beneficial roles for the host, such as supporting nutrient metabolism. In order to peacefully co-exist with the intestinal microflora the immune system has evolved multiple mechanisms through which it suppresses inflammatory immune responses against commensal bacteria, which together generate a tolerogenic environment. A breakdown in this tolerance can result in the onset of chronic inflammatory disorders such as Inflammatory Bowel Disease (and colon cancer), hepatitis, and rheumatoid arthritis.

Innate lymphoid cells (ILCs) play key roles in mediating intestinal immune homeostasis and maintaining healthy host-commensal bacteria interactions via the production of cytokines, interactions with other tissue-resident immune cell populations and the orchestration of local immune responses. In particular, recent studies have demonstrated that group 3 innate lymphoid cells are able to prevent intestinal inflammation by controlling the activation of commensal bacteria-specific inflammatory T cells in an antigen-specific manner (Hepworth et al Nature 2013, Science 2015).

This project will investigate i) how ILCs interact with intestinal immune cells to regulate responses to commensal bacteria ii) which bacterial species preferentially drive intestinal inflammation following disruption of ILC regulatory function(s) and iii) the specificity of ILC-regulation of inflammatory responses.

The project will utilize a range of approaches including the use of animal models, immunological techniques (flow cytometry, ELISA), molecular biology (PCR, sequencing) and microbiological methods to investigate interactions between the host immune system and the commensal microbiota in the context of health and disease.

The student will my join my laboratory located within the world-class Faculty of Life Sciences at the University of Manchester and will have access to a wide range of facilities and expertise across the faculty.

 

  • Hooper LV, Littman DR and MacPherson AJ. Interactions between the microbiota and the immune system. Science 2012 June 8; 336(6086)
  • Belkaid Y and Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014 Mar 27; 157(1)
  • Hepworth MR et al Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells Science 2015 May 29; 348(6238)
  • Hepworth MR et al Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria Nature 2013 Jun 6; 498(7452)
  • Palm NW et al Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease Cell 2014 Aug 28; 158(5)

 

Studies on food borne pathogens of man- how does Listeria monocytogenes survive inside the host intestine?

Listeria monocytogenes is a facultative intracellular Gram positive bacterium and the aetiological agent of Listeriosis a serious food borne disease. In contrast to other food borne infections, Listeriosis has high mortality rates (20-30%) despite antibiotic intervention. Infection can be perinatal where disease may manifest as listeric abortion, stillbirth or late-onset neonatal meningitis. In contrast, listeric infection in non-pregnant individuals usually affects the central nervous system manifesting as either meningitis or meningoencephalitis and atypically as endocarditis and pneumonia. In the case of immunocompromised patients, L. monocytogenes is the most commonly encountered form of bacterial meningitis with mortality rates as high as 60%. The incidence of listeriosis is increasing in the elderly population and with an expanding aged population the control of listeriosis remains an emerging priority. The principal mode of transmission of L. monocytogenes to humans is the ingestion of contaminated food with unpasteurized diary products, uncooked vegetables and chilled processed meat products being the main sources of infection. There have been a number of well-documented cases of food borne Listeriosis and globally, Listeriosis accounts for 30% of all fatalities as a consequence of food borne infection. As such L. monocytogenes represents a serious food-borne pathogen, which based on changing demographics and life style will pose an increasing risk. The project aims to use molecular microbial genetics, cell biology and metabolomics to study the survival and adaptation of  L. monocytogenes to its transit through the small intestine prior to invasion.

 

  • Corbett, D., Schuler, S., Glenn, S.,  Andrew, P. W.,  Cavet, J. S., Roberts, I. S. (2011) The combined actions of the copper-responsive repressor CsoR and copper-metallochaperone CopZ modulate CopA-mediated copper efflux in the intracellular pathogen Listeria monocytogenes. Mol. Microbiol.  81:457-472.
  • Corbett, D., Wang, J., Schuler, S., Lopez-Castejon, G., Glenn, S., Brough, D., Andrew, P.W., Cavet, J.S., Roberts, I.S. (2012) Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes During Growth in vitro and in vivo. Infect Immun. 80:14-21.
  • Lopez-Castejon G, Corbett D, Goldrick M, Roberts IS, Brough D, (2012) Inhibition of Calpain blocks the phagosomal escape of Listeria monocytogenes PLoS ONE 7:e35936
  • Corbett, D, Goldrick, M., Fernandes V. E., Davidge, K., Poole R. K., Andrew P. W., Cavet J., Roberts I. S. (2017).Listeria monocytogenes has both a bd-type and an aa3 -type terminal oxidase which allow growth in different oxygen levels and both are important in infection.(2017). Infect. Immun. 85:e00354-17 doi: 10.1128/IAI.00354-17

Studies on pathogenic Escherichia coli responsible for extra-intestinal infections of man

Escherichia coli are responsible for a number of serious extra-intestinal infections of man. These range from urinary tract infections through to septicaemia and meningitis. Often these E. coli are resistant to many antibiotics. The expression of cell surface structures such as the polysaccharide capsule or K antigen, is important during infection and growth in the host. These structures are important in mediating interactions between the pathogen and its immediate environment in the host. Specifically the expression of a K antigen is important in protecting the E. coli from killing by the host’s innate immune response. The project will focus in understanding how expression of the polysaccharide capsule is mediated during growth on and in host uroepithelial cells following invasion. The project will use state of the art genomics methodologies such as RNAseq as well as advanced live cell imaging.

  

  • Corbett, D., Roberts, IS. (2009). The role of microbial polysaccharides in host-pathogen interaction. F1000 Biology Reports 2009, 1:30 (doi: 10.3410/B1-30)
  • Hafez, M., Hayes, K., Goldrick, M., Warhurst, G., Grencis, R., Roberts, I. S. (2009). The K5 capsule of Escherichia coli strain Nissle 1917 is important in mediating interactions with intestinal epithelial cells and chemokine induction. Infect. Immun. 77: 2995-3003.
  • Hafez, M., Hayes, K., Goldrick, M., Grencis, R., Roberts, I. S. (2010). The K5 capsule of Escherichia coli strain Nissle 1917 is important in stimulating expression of TLR5, CD14, MyD88 and TRIF together with the induction of IL-8 expression via the MAPK-pathway in epithelial cells. Infect. Immun. 78:2153-2162
  • Thompson, J. E., Pourhossein, M.,  Waterhouse, A., Hudson, T., Goldrick, M., Derrick, J. P., Roberts. I. S. (2010). The K5 lyase KflA combines a viral tail spike structure with a bacterial lyase mechanism. J. Biol. Chem. 285: 23963-23969.
  • King, J. E., Aal Owaif H. A.,Jia, J.,Roberts, I. S. (2015). Phenotypic Heterogeneity in Expression of the K1 Polysaccharide Capsule of Uropathogenic Escherichia coliand its Down Regulation during Growth in Urine. Infect Immun.83:2605-13 

  • Jia, J., King, J. E., Goldrick, M., Aldawood, E., Roberts I. S. (2017).Three tandem promoters, together with IHF, regulate growth phase dependent expression of the Escherichia coli kpscapsule gene cluster. Sci. Reports 7:17924 doi:10.1038/s41598-017-17891-0