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Dr Stephen Chapman, Clinical Lecturer in Respiratory Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, and Oxford Centre for Respiratory Medicine, Radcliffe Hospitals, Oxford, United Kingdom

Dr Anna Rautanen, Post doctoral Research Scientist, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

In addition to tuberculosis, the group has a major interest in host genetic susceptibility to other severe respiratory infectious diseases, in particular invasive pneumococcal disease and thoracic empyema (a suppurative bacterial infection of the pleural space, which occurs as a severe complication of pneumonia). This research has been funded by the Wellcome Trust and performed in collaboration with Dr Derrick Crook at the Department of Microbiology, John Radcliffe Hospital, Dr Robert Davies at the Oxford Centre for Respiratory Medicine, and Professor Luke O’Neill at the School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. Previous study has utilised a population-based, case-control design using a candidate gene approach, focusing primarily on components of the Toll-like receptor-nuclear factor-kappaB signalling pathway. This pathway plays a critical role in the early recognition of invading pathogens and the initiation of a pro-inflammatory host response. Of particular note, a novel functional polymorphism within the gene encoding the Toll adaptor protein Mal/TIRAP was found to associate with protection against invasive pneumococcal disease, Gram-positive and Gram-negative bacteraemia, malaria and tuberculosis in different human populations.

Ongoing projects include the identification of additional genetic susceptibility loci for invasive pneumococcal disease, using both candidate gene and genome-wide approaches. The group has also recently been awarded a Wellcome Trust grant to perform a genome-wide association study of susceptibility to bacteraemia in childhood. This was awarded as part of the Wellcome Trust Case Control Consortium Phase II, and will be performed in collaboration with Dr Anthony Scott and Dr Thomas Williams at the Wellcome Trust Centre for Geographic Medicine Research, Kilifi, Kenya. Other major projects include the identification of susceptibility genes underlying community-acquired lower respiratory tract infection (as part of the European Commission Network of Excellence GRACE, ‘Genomics to combat resistance against antibiotics in community-acquired lower respiratory tract infection in Europe’) and outcomes from severe sepsis (GenOSept, ‘Genetics of Sepsis in Europe’, as part of the European Critical Care Network).

Khor CC*/Chapman SJ*/ Vannberg FO*, Hill AVS, O’Neill LAJ (* these authors contributed equally to this work). Reply to "Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations". Nature Genetics 2008; 40(3): 262-263.

Khor CC*/Chapman SJ*, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ,Kyrieleis O, Khan A, Aucan C, Segal S, Moore CE, Knox K, Campbell SJ, Lienhardt C, Scott A, Aaby P, Sow OY, Grignani RT, Peshu N, Williams TN, Davies RJO, Kwiatkowski DP, Day NP, Crook DW, Marsh K, Berkley JA,O’Neill LAJ*/Hill AVS* (* these authors contributed equally to this work). A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nature Genetics 2007; 39(4): 523-528. Reported as a ‘Research Highlight’ in Nature Medicine 2007; 13(4): 417, Nature Reviews Immunology 2007; 7 (4): 251, and Nature Reviews Microbiology 2007; 5(4): 244.

Chapman SJ, Vannberg FO, Khor CC, Segal S, Moore CE, Knox K, Day NP, Davies RJO, Crook DW, Hill AVS. Functional polymorphisms in the FCN2 gene are not associated with invasive pneumococcal disease. Molecular Immunology 2007; 44(12): 3267-3270.

Chapman SJ, Khor CC, Vannberg FO, Frodsham A, Walley A, Maskell NA, Davies CWH, Segal S, Moore CE, Gillespie SH, Denny P, Day NP, Crook DW, Davies RJO, Hill AVS. IkappaB genetic polymorphisms and invasive pneumococcal disease. American Journal of Respiratory and Critical Care Medicine 2007; 176: 181-187.

Chapman SJ, Khor CC, Vannberg FO, Maskell NA, Davies CWH, Hedley EL, Segal S, Moore CE, Knox K, Day NP, Gillespie SH, Crook DW, Davies RJO, Hill AVS. PTPN22 and invasive bacterial disease. Nature Genetics 2006; 38(5): 499-500.

Chapman SJ, Lee YCG, Davies RJO. Empyema, lung abscess and necrotising pneumonia. In: Torres A, Ewig S, Mandell L and Woodhead M, eds. Respiratory Infections. Hodder Arnold. First Edition, 2006.

Chapman SJ, Davies RJO. Pleural effusion: parapneumonic effusion and empyema. In: Laurent GJ and Shapiro S, eds. Encyclopedia of Respiratory Medicine. Elsevier. First Edition, 2006.

Chapman SJ, Robinson G, Stradling JR, West S. Oxford Handbook of Respiratory Medicine. Oxford University Press. First Edition, 2005.

Chapman SJ, Davies RJO. Recent advances in parapneumonic effusion and empyema. Current Opinion in Pulmonary Medicine 2004; 10: 299-304.

Chapman SJ, Davies RJO. Pleural effusion. Clinical Medicine 2004; 4(3): 207-210.

Chapman SJ, Davies RJO. The management of pleural space infections. Respirology 2004; 9(1): 4-11.

Roy S, Knox K, Segal S, Griffiths D, Moore CE, Welsh KI, Smarason A, Day NP, McPheat WL, Crook DW, Hill AVS, and the Oxford Pneumococcal Surveillance Group. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet 2002; 359: 1569-73.

Roy S, Knox K, Griffiths D, Crook D, Hill AVS. C reactive protein polymorphism is associated with susceptibility to invasive pneumococcal disease. BMJ 2002; 324: 1369.

The current project is to investigate candidate gene polymorphisms for association with severe malaria infection in a large set of Gambian cases and controls. Future work will involve the adoption of very high throughput techniques for genotyping using large numbers of single nucleotide polymorphisms.

Association of Fcgamma receptor IIa (CD32) polymorphism with severe malaria in West Africa. Cooke GS, Aucan C, Walley AJ, Segal S, Greenwood BM, Kwiatkowski DP, Hill AV. Am J Trop Med Hyg. 2003 Dec;69(6):565-8.

Common apolipoprotein E polymorphisms and risk of clinical malaria in the
Gambia. Aucan C, Walley AJ, Hill AV. J Med Genet. 2004 Jan;41(1):21-4.

Interleukin-1 gene cluster polymorphisms and susceptibility to clinical malaria in a Gambian case-control study. Walley AJ, Aucan C, Kwiatkowski D, Hill AV. Eur J Hum Genet. 2004 Feb;12(2):132-8.

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia. Aucan C., Walley A.J., Hennig B.J.W, Fitness J., Frodsham A., Zhang L., Kwiatkowski D. and Hill A.V.S. Genes Immun. 2003 Jun;4(4):275-82. Supplementary data.

Haptoglobin genotypes are not associated with resistance to severe malaria in The Gambia. Aucan C., Walley A.J., Greenwood B.M., Hill A.V. Trans R Soc Trop Med Hyg 2002;96(3):327-8.

1) Following a genome screen that was carried out in The Gambia and South Africa, this project aims to identify the putative tuberculosis susceptibility gene on the X chromosome through fine mapping and testing of positional candidate genes.

2) As part of an EU collaboration with laboratories in London, Italy, The Gambia, Guinee Conakry and Guinea Bissau, we are carrying out candidate gene studies. The aim is to replicate associations previously identified and to look at some new exciting candidates.

3) In collaboration with Professor Kumar (Cambridge) and Dr. Lamas (Birmingham), this project aims to locate a putative tuberculosis susceptibility locus in a three generation Caucasian pedigree.

Response heterogeneity of human macrophages to ATP is associated with P2X7 receptor expression but not to polymorphisms in the P2RX7 promoter. Li CM, Campbell SJ, Kumararatne DS, Hill AV, Lammas DA. FEBS Lett. 2002 Nov 6;531(2):127-31.

Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population. Li CM, Campbell SJ, Kumararatne DS, Bellamy R, Ruwende C, McAdam KP, Hill AV, Lammas DA. J Infect Dis. 2002 Nov 15;186(10):1458-62.

The Identification of Genetic Susceptibility factors for Tuberculosis . Campbell, S. J. (2001) Ph.D. Thesis, University of Oxford, UK

Fredrik Vannberg in collaboration with Professor Paul E. M. Fine, Sian Floyd, and Dr. Chris Wallace of the London School of Hygiene and Tropical Medicine

A two pronged strategy has been employed to investigate host genetic variants that may influence susceptibility to mycobacterial disease in this East African population. Case-control studies compare the prevalence of genetic variants in functional candidate genes between individuals that have the disease of interest (cases) and controls, who do not. The second approach utilises linkage analysis. A partial genome screen of 83 families containing 91 independent leprosy affected sibpairs has been completed using 114 microsatellite markers across 7 chromosomes (X, 5, 6, 9, 10, 15 and 21). Suggestive linkage (MLS>1) found at 10p13 and 21q22 is being investigated by addition of further markers in these regions.

Linkage analysis of susceptibility to leprosy type using an IBD regression method. Wallace C, Fitness J, Hennig B, Sichali L, Mwaungulu L, Ponnighaus JM, Warndorff DK, Clayton D, Fine PE, Hill AV. Genes Immun. 2004 Mar 11 PubMed

Genetics of susceptibility to leprosy. Fitness J., Tosh K. & Hill A.V. Genes Immun. 2002 Dec;3(8):441-53. PubMed PDF

Dr. Angela Frodsham, in collaboration with Professor Lon Cardon (WTCHG, Oxford), Professor David Clayton (CIMR, Cambridge) and Dr. Mark Thursz (Imperial College, London)

The aim of this project is to develop and use mathematical tools to aid the molecular approach in the elucidation of susceptibility genes for persistent HBV infection in regions identified in the previous genome scans performed as part of the RIO collaboration (see below).

Dr. Branwen Hennig (LSHTM, London) in collaboration with Dr. A Zaman, Prof. H Whittle, Dr. G Sirugo, Dr. M Mendy, Dr. M van der Sande, P. Waight and others (MRC Unit, The Gambia), Prof. Andy Hall and Dr. Katherine Fielding (LSHTM, London) and Prof. Adrian Hill (WTCHG, Oxford). This project aims to characterise genetic variants influencing long-term vaccine-induced immunity in HBV infection employing biological candidate genes. The outcome measures are vaccine-induced peak antibody levels (anti-HBs) and "breakthrough infection" (anti-HBc positivity). We have collected data on over 700 SNPs in more than 100 candidate genes, which were genotyped in a sample cohort from The Gambia consisting of 717 individuals vaccinated in infancy and followed for up to 18 years post-vaccination. Epidemiological and statistical analytical tools will be applied to assess the role of host genetic factors influencing immunity induced by infant vaccination to HBV in conjunction with other confounding factors, such as environmental factors.

(For more details see: http://www.lshtm.ac.uk/ideu/staff/bhennig.html and http://www.lshtm.ac.uk/ideu/research/ideu_research_detail.php?id=156)

The RIO project is a three way collaboration between the pharmaceutical company Roche, Dr Mark Thursz and Prof. Howard Thomas at Imperial College School of Medicine and Prof. Hill and Prof. Bell at the Wellcome Trust Centre for Human Genetics, Oxford. The project is to investigate the effect of host genetics on the outcome of infection with hepatitis B and C viruses.

We have used both a family and a more traditional case-control based analysis to investigate susceptibility to persistent hepatitis B virus infection. Two independent genome scans using affected sibling pairs who have persistent HBV infection from West Africa and Italy have been completed, and work is ongoing to investigate and identify the susceptibility genes in the regions identified by linkage analysis.

For the analysis of persistent HCV infection and disease we have a large collection of samples. Due to the additional information that we have on many of these samples, we can analyse such phenotypes as response to interferon alpha therapy and the rate of fibrosis, in addition to the outcome of HCV infection.

Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence.
Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A, Hennig BJ, Hellier S, Knapp S, Wright M, Chiaramonte M, Bell JI, Graves M, Whittle HC, Thomas HC, Thursz MR, Hill AV. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9148-53. Epub 2006 Jun 6. PubMed PDF

Host genetics and the outcome of hepatitis B viral infection.
Frodsham AJ. Transpl Immunol. 2005 Aug;14(3-4):183-6. Epub 2005 Apr 25. Review. PubMed PDF

Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection. Yee LJ, Knapp S, Burgner D, Hennig BJ, Frodsham AJ, Wright M, Thomas HC, Hill AV, Thursz MR. Genes Immun. 2004 Feb 26 PubMed PDF

Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P, Satsangi J, Wright M, Zhang L, Thomas HC, Thursz M, Hill AV. Hepatology. 2003 Dec;38(6):1468-76. PubMed PDF

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Knapp S, Yee LJ, Frodsham AJ, Hennig BJ, Hellier S, Zhang L, Wright M, Chiaramonte M, Graves M, Thomas HC, Hill AV, Thursz MR. Genes Immun. 2003 Sep;4(6):411-9. PubMed PDF

Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Knapp* S, Hennig* BJ, Frodsham AJ, Zhang L, Hellier S, Wright M, Goldin R, Hill AV, Thomas HC, Thursz MR. Immunogenetics. 2003 Sep;55(6):362-9. PubMed PDF

Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Wright M, Goldin R, Hellier S, Knapp S, Frodsham A, Hennig B, Hill A, Apple R, Cheng S, Thomas H, Thursz M. Gut. 2003 Aug;52(8):1206-10. PubMed PDF

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection. Hennig BJ, Hellier S, Frodsham AJ, Zhang L, Klenerman P, Knapp S, Wright M, Thomas HC, Thursz M, Hill AV. Genes Immun 2002 Sep;3(6):359-67. PubMed PDF

The Genetics of Susceptibility to Chronic Hepatitis Infection. Frodsham, A. (2000) Ph.D thesis, University of Oxford, UK.

Host Genetics of HIV-1 Infection and Disease Progression in Uganda. Ramaley, P. (2000). Ph.D thesis, University of Oxford, UK

Chemokine-receptor genes and AIDS risk. Ramaley, P.A., French, N., Kaellebu, P., Gilks, C., Whitworth, J. and Hill, A. V. S.(2002) Nature 417:140

For more than ten years we have been making and testing vaccines designed to induce T cell responses to the antigens we encode, chiefly using antigens from malaria and tuberculosis. We have had most success with heterologous prime-boost regimes using either a DNA vaccine or recombinant fowlpox or adenovirus to prime a response and recombinant MVA to boost it. Several of the vaccines we have developed have progressed into clinical trials (webpage). We continue to work on finding the most efficient way to induce a protective T cell response by vaccination and are exploring a number of novel ways to do this.

DNA-based vaccines for malaria: a heterologous prime-boost immunisation strategy. Hill AV, Reece W, Gothard P, Moorthy V, Roberts M, Flanagan K, Plebanski M, Hannan C, Hu JT, Anderson R, Degano P, Schneider J, Prieur E, Sheu E, Gilbert SC. (2000) Dev Biol (Basel). 104, 171-179.

Enhanced immunogenicity of CD4(+) T-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. McShane, H., Brookes, R., Gilbert, SC., Hill AV. (2001) Infect. Immun. 69 681-686.

pSG.MEPfTRAP – A first generation malaria DNA vaccine vector. Schneider, J., Gilbert, SC. and Hill, AVS. Chapter in Plasmids for Therapy and Vaccination ed Schleef, M. Wiley-VCH 2001.

Virus-like particles as vaccine adjuvants. Gilbert, SC. (2001) Molecular Biotechnology 19,169 – 177.

Enhanced CD8 T cell immunogenicity and protective efficacy in a mouse malaria model using a recombinant adenoviral vaccine in heterologous prime-boost immunisation regimes. Gilbert, SC., Schneider, J., Hannan, CM., Hu JT., Plebanski, M.,Sinden, R. and Hill, AVS. (2002) Vaccine 20, 1039-1045.

Competition between CTL narrows the immune response induced by prime-boost vaccination protocols. Palmowski MJ, Choi EM, Hermans IF, Gilbert SC, Chen JL, Gileadi U, Salio M, Van Pel A, Man S, Bonin E, Liljestrom P, Dunbar PR, Cerundolo V. (2002) J Immunol. 168, 4391-4398.

Heterologous Prime-Boost Immunisation of cattle with mycobacterium tuberculosis 85A induces antigen-specific T cell responses. Taracha,ELN., Bishop,R., Musoke, AJ., Hill, AVS., Gilbert, SC. (2003) Infection and Immunity. 71(12):6906-14.

A Plasmodium Falciparum Candidate Vaccine Based On A Six Antigen Polyprotein Encoded By Recombinant Poxviruses. Prieur, E, Gilbert, SC, Schneider, J, Sheu, EG, Goonetilleke, N, Robson, KJH and Hill, AVS. (2004) PNAS 101: 290-295.

Enhanced CD8+ T-cell immune responses and protection elicited against Plasmodium berghei malaria by prime boost immunisation regimes using a novel attenuated fowlpox virus. Anderson, RJ, Hannan, CM, Gilbert, SC, Laidlaw, SM,. Sheu, EG, Korten, S, Sinden, R, Butcher, GA, Skinner, MA and Hill, AVS.(2004) J Immunol. 172:3094-100.

Cellular immune responses in cattle induced after heterologous prime-boost vaccination based on recombinant viruses and BCG. Vordermeier, HM, Rhodes, SG, Dean, G, Goonetilleke, N, Huygen, K, Hill, AVS,Hewinson, RG and Gilbert, SC.(2004) Immunology 112: 461-470.

Dendritic cells infected by modified Vaccinia virus Ankara retain immunogenicity in vivo despite in vitro disfunction. Behboudi, S, Moore, A, Gilbert, SC, Nicoll, C and Hill, AVS.(2004) Vaccine. 22(31-32):4326-31.

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence. Smith CL, Dunbar PR, Mirza F, Palmowski MJ, Shepherd D, Gilbert SC, Coulie P, Schneider J, Hoffman E, Hawkins R, Harris AL, Cerundolo V. (2005) Int J Cancer. 113:259-66.

Inverse Associations Of HLA And Malaria Parasite Type In Two West African Populations. Young, K, Frodsham, AJ, Doumbo, OK, Gupta, S, Dolo, A, Hu, JT, Robson, KJH, Crisanti, A, Hill, AVS, Gilbert, SC. (2005) Infection and Immunity 73: 953-5

Quantitative Real-Time PCR For Malaria Diagnosis And Its Use In Malaria Vaccine Clinical Trials. Andrews, L, Andersen, RF, Webster, D, Dunachie, S, Walther, RM, Bejon, P, Hunt-Cooke, A, Bergson, G, Sanderson, F, Hill, AVS, Gilbert, SC. (2005) Am. J. Trop. Med. Hyg. 73: 191-8.

Novel Protein and Poxvirus Based Vaccine Combinations for Simultaneous Induction of Humoral and Cell Mediated Immunity. Hutchings CL, Gilbert SC, Moore AC, and Hill AVS. (2005) J. Immunol. 175: 599-606.

Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Williams A, Goonetilleke NP, McShane H, Clark SO, Hatch G, Gilbert SC, Hill AV. (2005) Infect. Immun. 73: 3814-6.

Anti CD25 Antibody Enhancement of Vaccine-Induced Immunogenicity: Increased Durable Cellular Immunity with Reduced Immunodominance. Moore AM, Gallimore A, Draper S, Watkins KR, Gilbert SC and Hill AVS. (2005) J. Immunol. 175: 7264-73

Khor CC*/Chapman SJ*/ Vannberg FO*, Hill AVS, O’Neill LAJ (* these authors contributed equally to this work). Reply to "Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations". Nature Genetics 2008; 40(3): 262-263.

Khor CC/Chapman SJ/ Vannberg FO, Hill AVS, O’Neill LAJ ( these authors contributed equally to this work). Reply to "Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations". Nature Genetics 2008; 40(3): 262-263.