Infectious diseases research encompasses basic studies on viruses, bacteria and host immune responses.
Dr Sergey Nejentsev’s group investigates genetic and functional mechanisms of susceptibility to infection. The group is conducting large genome-wide association studies aiming to identify human variants that control immune responses to M. tuberculosis infection and predispose to pulmonary TB. The group also studies patients with primary immunodeficiencies using whole exome sequencing to discover new causative mutations, followed by detailed functional analyses of the affected cellular pathways.
Professor Sharon Peacock’s group aims to introduce high-throughput whole genome sequencing technologies into diagnostic and public health microbiology for outbreak investigation and to optimise antimicrobial therapy of individual patients. She works in close collaboration with the Wellcome Trust Sanger Institute and the Health Protection Agency.
Professor John Sinclair’s group studies how human cytomegalovirus (HCMV) persists in healthy individuals studying cellular factors which control virus latency and reactivation. Dr Wills’ group, with Professor Sissons, study the control of HCMV infection by the immune system. In collaboration, their work on latent carriage of the virus and host immune responses to latent infection has now identified changes in the latently infected cells which can act as targets for novel chemotherapeutic and immunotherapeutic strategies with an aim to clearing latent infection in some clinical settings.
Professor Andrew Lever’s group studies retroviruses, including structural and molecular studies of RNA and RNA:protein interactions involved in genome encapsidation and the development of gene vectors. He and Dr Desselberger are investigating rotavirus RNA structures involved in encapsidating the viral genome and which host cell proteins or organelles may interact with the virus and be involved in viral assembly.
Dr Lydia Drumright’s group takes a multidisciplinary approach to infectious disease epidemiology integrating classical and molecular epidemiology with clinical informatics, statistical and mathematical modelling, and behavioural and environmental sciences. This systems-level way of thinking helps to maximise our understanding of how infectious diseases are transmitted, resulting in more effective interventions. Recent work includes the characterisation of norovirus transmission dynamics within healthcare settings, and the use of electronic hospital data for infectious disease surveillance.
Dr Yorgo Modis’s groups goal is to gain a mechanistic understanding at the molecular level of how important pathogens interact with their host cells during infection. We seek to understand the following major questions: (1) How do enveloped viruses assemble and recognize host cells? (2) How do enveloped viruses deliver their genome into the cytoplasm? (3) What are the evolutionary origins of the genes that drive virus entry? (4) How are innate immune responses to microbial nucleic acids generated, amplified and regulated? To answer these questions, we are employing a diverse set of complementary biophysical, biochemical and cell biological approaches. By integrating approaches across scales (in space and time), we envision moving towards a structure-based understanding of biological processes at the cellular level. Each of our projects has important potential applications in global health.
Nour AM, Li Y, Wolenski J, Modis Y (2013) Viral membrane fusion and nucleocapsid delivery into the cytoplasm are distinct events in some flaviviruses. PLoS Pathog. 9:e1003585.
Li Y, Wang J, Kanai R, Modis Y (2013) Crystal structure of glycoprotein E2 from bovine viral diarrhea virus. Proc. Natl. Acad. Sci. U.S.A., 110:6805-10.
Dessau M & Modis Y (2013) Crystal structure of glycoprotein C from Rift Valley fever virus. Proc. Natl. Acad. Sci. U.S.A. 110:1696-701.
Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013; 342 (6160): 866-71.
Weekes MP, Tan SYL, Poole E, Talbot S, Antrobus R, Smith DL, Montag C, Gygi SP., Sinclair JH, Lehner PJ. Latency-associated degradation of the MRP1 drug transporter offers a therapeutic target for latent human cytomegalovirus (HCMV) infection. Science 340, 199–202 (2013).
Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, Balabanova Y, Ehmen C, Muntau B, Ruge G, Sievertsen J, Gyapong J, Nikolayevskyy V, Hill PC, Sirugo G, Drobniewski F, van de Vosse E, Newport M, Alisjahbana B, Nejentsev S, Ottenhoff TH, Hill AV, Horstmann RD, Meyer CG. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat Genet. 2012; 44 (3): 257-9.
Köser CU, Bryant JM, Becq J, Török ME, Ellington MJ, Marti-Renom MA, Carmichael AJ, Parkhill J, Smith GP, Peacock SJ. Whole-genome sequencing for rapid susceptibility testing of M. tuberculosis. New Engl J Med. 2013;369:290-292.
Harris SR, Cartwright EJP, Török ME, Holden MT, Brown NM, Ogilvy-Stuart AL, Ellington MJ, Quail MA, Bentley SD, Parkhill J, Peacock SJ. Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect Dis. 2013;13:130-6.
Mason GM, Jackson S, Okecha G, Emma Poole, Sissons, JGP, Sinclair JH and Wills MR (2013) Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4+ T cells. Plos Pathogens 2013;9(10):e1003635.
Mason GM, Poole E, Sissons JG, Wills MR, and Sinclair JH. (2012) Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Proc Natl Acad Sci USA 109:14538–14543.
Stephenson JD, Li H, Kenyon JC, Symmons M, Klenerman D, Lever AML. 3D RNA structure of the major HIV-1 packaging signal region. Structure 2013; 21(6): 951-962
Kenyon JC, Prestwood LJ, Le Grice SFJ, Lever AML. In-gel probing of individual RNA conformers within a mixed population reveals a dimerisation structural switch in the HIV-1 leader. Nucleic Acids Research 2013; 1-11.
Richards JE, Desselberger U, Lever AM. Experimental pathways towards developing a rotavirus reverse genetics system: synthetic full length rotavirus ssRNAs are neither infectious nor translated in permissive cells. PLoS One. 2013 Sep 3;8(9):e74328
Desselberger U, Huppertz HI. Immune responses to rotavirus infection and vaccination, and associated correlates of protection. J Infect Dis 2011; 203: 188-195.
Bennett NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G, Eagle RA, Trowsdale J, Sissons JG, Wills MR (2010) Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus J Immunol Jul 15; 185(2): 1093-102
Ashiru O, Bennett NJ, Boyle LH, Thomas M, Trowsdale J, Wills MR NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142 J Virol Dec; 83(23): 12345-54
Rizvi TA, Kenyon JC, Ali J, Aktar SJ, Phillip PS, Ghazawi A, Mustafa F, Lever AM (2010) Optimal Packaging of FIV Genomic RNA Depends upon a Conserved Long-range Interaction and a Palindromic Sequence within gag J Mol BiolAug 21. [Epub ahead of print]
Reeves M, Woodhall D, Compton T, Sinclair J (2010) Human cytomegalovirus IE72 protein interacts with the transcriptional repressor hDaxx to regulate LUNA gene expression during lytic infection. J Virol Jul; 84(14): 7185-94
Li W, Manktelow E, von Kirchbach JC, Gog JR, Desselberger U, Lever AM (2010) Genomic analysis of codon, sequence and structural conservation with selective biochemical-structure mapping reveals highly conserved and dynamic structures in rotavirus RNAs with potential cis-acting functions Nucleic Acids Res Jul 29. [Epub ahead of print]
Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW (2010) Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivoCirc Res Jul 23; 107(2): 252-62
Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare Variants of IFIH1, a Gene Implicated in antiviral responses, protect against type 1 diabetes Science Apr 17; 324(5925): 387-9 link to abstract
Poole E, Groves I, MacDonald A, Pang Y, Alcami A, Sinclair J (2009) Identification of TRIM23 as a cofactor involved in the regulation of NF-kappaB by human cytomegalovirus J Virol Apr; 83(8) :3581-90
Kenyon JC, Ghazawi A, Cheung WK, Phillip PS, Rizvi TA, Lever AML (2008) The secondary structure of the 5′ end of the FIV genome reveals a long-range interaction between R/U5 and gag sequences, and a large, stable stem-loopRNA Dec;14(12):2597-608
Reeves, MB, Davies, AA, McSharry, BP, Wilkinson, GW and Sinclair JH (2007) Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death Science 316: 1345-1348.
Goodrum, FD, Reeves, M, Sinclair, J , High, K and Shenk, T (2007) Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro Blood in press
Waller, EC, McKinney N, Hicks, R, Carmichael AJ, Sissons JG , and Wills MR (2007) Differential co-stimulation through CD137 (4-1BB) restores proliferation of human virus-specific “effector memory” (CD28-CD45RAhi) CD8+ T Cells. Blood
Day, EK, Carmichael AJ , ten Berge IJ, Waller EC, Sissons JG , and Wills MR (2007). Rapid CD8+ T Cell Repertoire Focusing and Selection of High-Affinity Clones into Memory Following Primary Infection with a Persistent Human Virus: Human Cytomegalovirus J Immunol 179: 3203-3213
Poole, E, King, C, Sinclair, J and Alcami, A (2006) The UL144 gene product of human cytomegalovirus activates NF_B via a TRAF6-dependent mechanism. EMBO J. 18: 4390-4399
Anderson, EC, Lever, AML (2006) HIV-1 Gag polyprotein modulates its own translation Journal of Virology ; 80 10478-10486
Poole, E, E, Strappe, P, Mok, H-P, Hicks, R, Lever, AML (2005) HIV-1 Gag-RNA interaction occurs at a perinuclear/centrosomal site; analysis by confocal microscopy and FRET Traffic 6: 741-55
Zhao, J, Pettigrew, GJ, Bolton, EM, Murfitt, CR, Carmichael, AJ, Bradley, JA, Lever AML (2005) Lentivirus-mediated gene transfer of viral interleukin delays but does not prevent cardiac allograft rejection. Gene Therapy 12: 1509-1516
Matthew Reeves, Paul MacAry, Paul Lehner , Patrick Sissons and John Sinclair (2005) Latency, Chromatin Remodelling and Reactivation of Human Cytomegalovirus in the Dendritic Cells of Healthy Carriers Proceedings of the National Academy of Sciences (USA) 102: 4140-4145
Zeffman, A, Hassard, S, Varani G, Lever AML (2000) The major HIV-1 packaging signal is an extended bulged stem loop whose structure is altered on interaction with the Gag polyprotein J Mol Biol 297: 877-893