Infection Supervisors
Theme Leader: Professor Charles Bangham
Charles Bangham
Human retroviral infection: immune response and persistence
The human leukaemia virus HTLV-1 causes a chronic inflammatory disease of the central nervous system or a rapidly fatal leukaemia in 5-10% of infected individuals, but remains asymptomatic in 90%. The aim of our work is to understand how HTLV-1 persists in the host despite a strong immune response and why it causes these fatal or disabling diseases in certain individuals. We use techniques in cellular and molecular immunology, host and viral genetics, gene expression microarrays, cell biology and mathematics. Our major contributions include the discovery of the virological synapse (Science 2003: 299, 1713-6) - a novel mechanism of direct cell-cell spread of viruses.
Recent reviews:
- Bangham, C. R. M. 2008. Genetic susceptibility in infection with human T-lymphotropic virus type 1 (HTLV-1). Ch. 20, pp. 303-317, in Genetic Susceptibility to Infection, eds. R. Kaslow, J. McNicholl, A. Hill. Oxford University Press.
- Bangham, Charles R. M., Kiran Meekings, Frederic Toulza, Becca Asquith and Graham P Taylor. 2009. The immune control of HTLV-1 infection: selection forces and dynamics. Frontiers in Bioscience 14, 2889-2903.
- Bangham, C. R. M. 2009. CTL quality and the control of human retroviral infections. [Invited review]. Eur. J. Immunol. 39, 1700-1712.
- Nejmeddine, M. and Charles R. M. Bangham. 2010. The HTLV-1 virological synapse. [Invited review]. Viruses 2(7), 1427-1447. http://www.mdpi.com/1999-4915/2/7/1427/pdf.
Further Information: http://www1.imperial.ac.uk/medicine/people/c.bangham/
Contact Details
c.bangham@imperial.ac.uk
Tel: +44 (0) 207 594 3730
Martin Allday
Summary of Research Interests:
We are interested in the circumstances that lead to the development of virus-associated cancers and specifically the contribution Epstein-Barr virus (EBV) makes to the pathogenesis of various human B cell lymphomas. We are trying to understand how this relates to normal persistence of the virus in a latent form and to determine whether the virus can provide specific targets for therapeutic intervention.
Using bacterial artificial chromosome (BAC) technology, we recently showed that EBNA3A and EBNA3C cooperate to repress the transcription of the pro-apoptotic, Bcl-2-family member Bim and enhance B cell survival4,5. This has established a molecular link between EBV latency and the pathogenesis of Burkitt's lymphoma (BL)5. We have also been investigating precisely how EBV inactivates p53-independent cell cycle checkpoints associated with DNA and chromosome damage and how it interferes with the function of the cyclin dependent kinase inhibitor p21WAF1 and its target cdk21,3,4. This has led us into a study of how p21WAF1 is normally regulated in B cells and how the turn-over of proteins such as p21WAF1 and pRb is regulated2.
Having identified a tumour suppressor gene, Bim, as a target for epigenetic repression by EBV (manuscript submitted), it is important to establish whether other genes expressed in B cells can be reprogrammed in a similar way. Consequently we have embarked on a project to investigate the epigenome of B cells latently infected with EBV. We are also about to start a clinical study of lymphoma specimens to determine to what extent EBV epigenetically re-programmes cells during B lymphomagenesis in immunosuppressed individuals.
Using the panel of recombinant EBV BACs with modified EBNA3 genes that we have generated5, transcription profiling using Affymetrix Exon chips has shown that around 1000 genes are regulated by the EBNA3s (EBNA3A, EBNA3B and EBNA3C). Most strikingly there appears to be an enormous amount of cooperation between the three proteins, with regulation of around half of the differentially expressed genes being dependent on more than one EBNA3 protein. We are using bioinformatic and biochemical approaches to dissect the B cell growth, differentiation and survival pathways that are regulated by latent EBV and the EBNA3s in particular.
With all the various recombinant EBV BACs we have constructed (>12) our longer-term aim is to establish an in vivo model system using humanized immunodeficient mice to assess the role of individual EBV gene products in EBV persistence in B cells and B lymphomagenesis.
Selected publications:
1. O'Nions, J. & Allday, M.J. (2003). Epstein-Barr virus can inhibit genotoxin-induced G1 arrest downstream of p53 by preventing the inactivation of CDK2. Oncogene 22, 7181-7191.
2. Sdek, P., Ying, H., Chang, D., Qiu, W., Zeng, H., Touitou, R. Allday, M.J. & Xiao, J. (2005). MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Molecular Cell, 20, 699-708.
3. O'Nions, J., Turner, A., Craig, R. & Allday, M.J. (2006). Epstein-Barr virus selectively regulates the DNA-damage responses of normal B cells, but has no detectable effect on the tumour suppressor p53. J. Virol. 80,12408-13.
4. Leao, ME., Anderton, E., Wade, M., Meekings, K. & Allday, M.J. (2007). Epstein-Barr virus (EBV)-induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt's lymphoma cells. J. Virol. 81, 248-60.
5. Anderton, E., Yee, J., Smith, P., Crook, T., White, R. & Allday, M.J. (2008) Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the pro-apoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. Oncogene 17, 421-33. [ePubMed., 2007 Jul 23].
Further Information: http://www1.imperial.ac.uk/medicine/about/divisions/is/viro/oncoherp/
Contact Details
m.allday@imperial.ac.uk
Tel: +44 (0)20 7594 3836
Jonathan Friedland
Matrix metalloproteinases and the pathogenesis of tuberculosis
The focus of my research group is on (1) The regulation of matrix metalloproteinases (MMPs) and their specific inhibitors in tuberculosis (2) Novel diagnostics in tuberculosis. I also have an interest in the role of MMPs in neurocysticercosis.
TB is a disease which kills 2 million people a year and in which there is increasing drug resistance. Pathology is due more to the human innate immune response than to the pathogen. Research focus is on the role of intercellular networks as well as upstream and transcriptional regulation of MMP secretion and factors that drive development of a matrix degrading phenotype in TB. MMPs are investigated using primary human cells and samples from TB patients. The medium term aim is to develop novel therapeutic approaches to TB. The Tuberculosis Research Group is based on the Hammersmith campus of Imperial College and has good collaborations with overseas units. My group has an excellent track record in supporting potential academic clinicians and helping them obtain Wellcome / MRC Training and Intermediate Fellowships. I am very happy to see any potential candidates and chat through their options and clarify the processes and pitfalls of such applications – just send an email.
Further Information
http://www1.imperial.ac.uk/medicine/people/j.friedland/
http://www1.imperial.ac.uk/departmentofmedicine/divisions/infectiousdiseases/idi/training/fellows/
Contact Details
Tel: +44 (0)20 8383 8521
David Holden
Bacterial genetics and pathogenesis
Our group studies molecular aspects of Salmonella pathogenesis, focusing in particular on a specialised multi-protein machine known as a type III secretion system (T3SS), which translocates effector proteins from intracellular bacteria across phagosomal membranes into host cells. The effectors help to create a specialised compartment - the Salmonella-containing vacuole (SCV), which permits bacterial replication in host cells. At least three effectors are involved in regulating vacuolar membrane dynamics. Other effectors influence trafficking of the SCV in relation to the endocytic pathway, and cause the assembly of an F-actin meshwork around the SCVs. We discovered that an effector called SseG is required for localisation of SCVs close to the Golgi network in epithelial cells, and that close association between SCVs and the Golgi network is necessary for intracellular bacterial replication. We recently found a new effector that functions as a deubiquitinase, and another that functions as a phosphothreonine lyase acting on ERK.
Our current research involves a multi-disciplinary approach, using molecular genetics, biochemistry and cell biology, to understand the functions of these and other effectors, and how their collective action enables the intracellular replication of the pathogen.
Further information: http://www3.imperial.ac.uk/cmmi/research/holden
Contact Details
d.holden@imperial.ac.uk
Tel: +44 (0)20 7594 3073
Salim Khakoo
My research program is geared towards understanding how natural killer (NK) cells and diversity in NK cell receptors and their ligands define the immune response to viral infections in general, and hepatitis C virus in particular. We made the observation that inhibitory NK cell receptor diversity can determine the outcome of the immune response to HCV (Science 2004, 872-874). Work in my group is focused on understanding the mechanism of this protection and also on understanding the broader role of natural killer cells in acute and chronic hepatitis C virus infection. We are achieving this by studying basic mechanisms in vitro and then applying these ideas to the study of patients with acute and chronic HCV infection. Our overall aim is to use this data to understand the NK cell response to viruses and to inform therapy for HCV. Our work has a number of themes, the majority of which is funded by a Wellcome Trust Senior Clinical Fellowship.
Our work falls into three broad categories:
1. Understanding NK receptor binding and function
In order to understand the role of killer immunoglobulin-like receptors (KIR) diversity in the outcome of HCV infection, we are studying the basic mechanism of how these receptors interact with MHC class I, how changes in MHC class I peptides can influence KIR binding and how the allelic diversity of KIR can affect this.
2. NK receptor studies in individuals with chronic HCV infection
The binding studies are used to inform genetic studies of patients with HCV, and the allelic diversity of both KIR, which hitherto has only been studied at the level of the locus, and of MHC class I. We have recently completed a study of the role of KIR and MHC class I in treatment-induced resolution of HCV, the results of which are consistent with our previous findings in spontaneously resolving HCV infection. We believe that the activating and inhibitory signals of NK cells are not balanced correctly in HCV and we are interested in understanding how NK cells are balanced, in general, and how this is disturbed in HCV infection.
3. Generating new reagents to study natural killer cells
One of the goals of the group is to move towards adoptive NK cell immunotherapy. In order to perform this we are generating novel single-chain antibodies against NK cell receptors and also have a collaborative project studying NK cells in human umbilical cord blood, which we believe could be a viable source of NK cells for this work.
Further information: http://www1.imperial.ac.uk/medicine/people/s.khakoo/
Contact Details
s.khakoo@imperial.ac.uk
Ajit Lalvani
Tuberculosis: diagnosis, host response and epidemiology
Contact Details
a.lalvani@imperial.ac.uk
Tel: +44 (0)20 7594 0883
Michael Levin
Paediatric Infectious Diseases Group
The paediatric infectious diseases group headed by Professor Michael Levin is applying genetic, genomic and proteomic methods to understanding of the immunopathogenesis of a number of life threatening infections in childhood. Current programmes focus on meningococcal septicaemia and meningitis, childhood tuberculosis, Kawasaki disease, severe respiratory infection and H1N1 infection and severe malaria and septic shock in Africa. The department has large scale DNA and RNA collections from patient cohorts with all of these diseases and is linking genomic and genetic approaches to understanding disease mechanisms in close collaboration with statistical and mathematical expertise in the Department of Mathematics and Statistical Genomics.
PhD projects would be available on any of the diseases mentioned, focused on unravelling the immunopathogenesis and susceptibility.
The research group also has an interest in Mandelian defects causing susceptibility to unusual infection in childhood and has ongoing research interests in the interferon-gamma and IL12 pathway defects predisposing to mycobacterial infection.
Further information: http://www1.imperial.ac.uk/medicine/people/m.levin/
Contact Details
m.levin@imperial.ac.uk
Tel: +44 (0)20 7594 3760
Peter Openshaw
Respiratory viral infections
There are many unsolved puzzles in RSV research. Why do children that recover from bronchiolitis often get asthma? Why does one infection not protect against the next? Is this because of viral evasion and persistence?
Openshaw's group works on RSV disease in mouse and man. He pioneered methods of comprehensive immunopathological profiling, showing in mice that the exact character of the immune response determines the rate of virus clearance and type of lung pathology that accompanies elimination of infection. His group now works on regulatory T cells, innate defences, vaccines and neonatal immunology. He is the Director of the Centre for Respiratory Infections.
References:
Harker, J., A. Bukreyev, P.L. Collins, B. Wang, P.J. Openshaw, and J.S. Tregoning (2007). Virally delivered cytokines alter the immune response to future lung infections. J. Virol. 81:13105-13111.
Moghaddam, A., W. Olszewska, B. Wang, J. S. Tregoning, R. Helson, Q. J. Sattentau, and P. J. Openshaw (2006). A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Nat. Med. 12:905-907.
Smyth,R.L. and P.J. Openshaw (2006). Bronchiolitis. Lancet 368:312-322.
Further Information
http://www1.imperial.ac.uk/medicine/people/p.openshaw.html
http://www1.imperial.ac.uk/medicine/cri
Contact Details
p.openshaw@imperial.ac.uk
Tel: +44 (0)20 7594 3854
Gavin Screaton
Emerging viral infections
Dengue virus is an emerging mosquito-borne disease affecting tropical and subtropical areas of the world and the incidence of disease has increased alarmingly in the last two decades. Dengue co-circulates as four distinct viral serotypes and immunity to one does not protect from infection by other viral serotypes. One of the fascinating features of dengue is that the more severe symptoms of the disease, leading to dengue haemorrhagic fever, usually occur in individuals who suffer a second or sequential infection.
We have a close collaboration with clinical sites in Thailand where clinical samples are obtained. The laboratory is interested in the immune response to dengue viruses both T cell mediated and antibody mediated with a view to understanding disease enhancement and immunopathology.
References
W.Dejnirattisai, T Duangchinda, C-L Lin, S Vasanawathana, M Jones, M Jacobs, P Malasit, X-N Xu, GR Screaton, J Mongkolsapaya. A complex interplay between virus, dendritic cells, T cells and cytokines in dengue virus infections. J Immunol. 2008 181: 5865-5874.
J Mongkolsapaya, T Duangchinda, W Dejnirattisai, S Vasanawathana, P Avirutnan, A Jairungsri, N Khemnu, N Tangthawornchaikul, P Chotiyarnwong, K Sae-Jang, M Koch, Y Jones, A McMichael, X Xu, P Malasit, GR Screaton. T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal? J Immunol. 2006 17: 3821-3829.
J Mongkolsapaya, W Dejnirattisai, X-N Xu, S Vasanawathana, N Tangthawornchaikul, A Chairunsri, S Sawasdivorn, T Duangchinda, T Dong, S Rowland-Jones, P Malasit, A McMichael, GR Screaton. Original antigenic sin and apoptosis in the pathogenesis of dengue haemorrhagic fever. Nature Med 2003 9: 921-927.
Further Information: http://www1.imperial.ac.uk/medicine/people/g.screaton/
Contact Details
g.screaton@imperial.ac.uk
Tel: +44 (0)20 8383 2002
Jonathan Weber
HIV
Contact Details
j.weber@imperial.ac.uk
Tel: +44 (0)20 7594 3901
Infections caused by Streptococcus pyogenes range from pharyngitis to invasive, lethal necrotising fasciitis. There is a strong imperative to increase research in this area, especially as the rate of invasive disease in the UK surged at the start of 2009. Research into the pathogenesis of S. pyogenes infection is bolstered by our collaboration with epidemiologists in the Health Protection Agency, with the Sanger Institute, and by our direct involvement in patient care.
Understanding the pathogenesis of infection transmission and progression will help to determine the best management strategies for preventing transmission and improving treatment in the future. Neutrophil recruitment is impaired during lethal S. pyogenes diseaseand this is in part related to the novel enzyme, SpyCEP (S. pyogenes Cell Envelope Proteinase) made by the bacterium, a protease that was discovered in this laboratory. Clearance of S. pyogenes is, however, impeded by a plethora of virulence mechanisms employed by the bacterium including hyaluronic acid capsule, proteins that bind to or inactivate complement and antibacterial peptides, and enzymes that degrade immunoglobulins. Projects addressing bacterial evasion of immune defence, as well as the role of superantigens in streptococcal infection are available in the laboratory.
Further information: http://www1.imperial.ac.uk/medicine/people/s.sriskandan/
Contact Details
s.sriskandan@imperial.ac.uk
Tel: +44 (0)20 8383 3135
Role of infection in acute exacerbations of asthma and COPD
My group tries to understand the causes and mechanisms of acute exacerbations of asthma and COPD in order to try to identify new treatment options for this major unmet clinical need. We have previously shown that viruses are the main precipitants (BMJ 1995, 1997, 2003, Lancet 2002, 2003) and that rhinoviruses are by far the major individual type involved. We successfully established human rhinovirus challenge models of acute exacerbations of both asthma (PNAS 2008) and COPD (AJRCCM 2010) and a novel experimental model of rhinovirus infection and of rhinovirus induced acute exacerbations of asthma in mice (Nature Med 2008).
We have recently discovered that people with asthma and COPD are more susceptible than normal people to rhinovirus infections, which seems to be explained by reduced interferon responses in vitro and in vivo (Lancet 2002, J Exp Med 2005 and Nature Med 2006). If asthma is a condition characterised by interferon deficiency, this clearly leads to the possibility of treating it with interferon's or by measures aimed at boosting interferon levels/responses in the lung. We are currently trying to understand why people with asthma and COPD have this deficiency.
We have also found a role for bacteria in acute exacerbations of asthma and COPD (BMJ 2010, AJRCCM 2008) and are currently investigating mechanism of host defence against bacterial infections in both diseases. We are also interested in testing new treatment options and recently showed that a ketolide antibiotic drug has remarkable and unexpected benefits in acute asthma (NEJM 2006).
Further Information: http://www1.imperial.ac.uk/medicine/people/s.johnston/
Contact Details
s.johnston@imperial.ac.uk
Tel: +44 (0)20 7594 3764
http://www1.imperial.ac.uk/medicine/people/r.shattock/
Contact details
Tel: +44 (0)207 7594 5206
