A partnership between the Universities of Brighton and Sussex with the NHS

 

infection and inflammation

Name: Professor Melanie Newport PhD FRCP MRCPCH

Academic position: Professor in Infectious Diseases & Global Health

Research: genetic regulation of immune responses and susceptibility to infectious disease, infant immune responses to vaccination, mycobacterial infection, susceptibility to podoconiosis (non-infectious geochemical elephantiasis)

Contact details:

Medical School Research Building
Brighton

E-mail:

Brighton and Sussex Medical School
University of Sussex
Falmer
Brighton BN1 9PS
UK

Tel: +44 (0)1273 877882
Fax: +44 (0)1273 877884

Biography:

• BSc (Genetics) 1983. University of London
• MBBS 1986 St Mary’s Hospital Medical School, University of London
• PhD (Medicine) 1996. University of London
• Clinician Scientist, Tuberculosis Group and Head of Human Genetics Laboratory, 1996-1999, MRC Laboratories, The Gambia
• MRC Linked Fellowship, 1999-2000, Department of Medicine, School of Clinical Medicine, University of Cambridge, UK
• Wellcome Trust Advanced Clinical Fellow and Honorary Consultant in Infectious Diseases, 2001-2004, University of Cambridge School of Clinical Medicine/Addenbrooke’s NHS Trust, Cambridge UK
• Senior Lecturer, then Reader in Infectious Diseases and International Health. 2004-present, Brighton and Sussex Medical School.
  

Teaching focus:

Infection and immunity: from basic science to clinical medicine.
International Health: at BSMS we recognise the importance of global health issues as we prepare doctors to work in a 'shrinking world'. Students are able to join our internationally-renowned researchers on their projects, and many use their elective to explore international health issues through personal experience.

Research focus:

Infectious diseases are a major cause of morbidity and mortality globally. However, only a minority of individuals develop clinical disease when infected by a given pathogen. Understanding the mechanisms of host resistance could lead to the development of much needed new or improved vaccines and therapies for infectious diseases, particularly HIV/AIDS, malaria and tuberculosis (TB). Genetic factors are key determinants of this resistance and my research aims to identify the specific genes and pathways involved that could be targets for novel intervention.

Current research:

The genetic basis of susceptibility to mycobacterial infection including tuberculosis
My interest in the field of genetic susceptibility to infectious disease began with the characterisation of the molecular basis of a novel immunodeficiency syndrome (disseminated atypical mycobacterial infection) in a group of related Maltese children, the basis of my PhD thesis. A mutation in the interferon-gamma receptor-1 gene was identified as the cause of disease in this family. This was the first gene to be associated with susceptibility to mycobacterial infection in humans, and subsequent studies in other similar families identified a number of other mutations both in this gene and other genes within the interleukin-12/interleukin-23/interferon-gamma pathway. This syndrome is now known as Mendelian susceptibility to mycobacterial disease (MSMD).  Whilst studies on rare Mendelian disorders identify critical components required for immunity to specific pathogens, they do not explain susceptibility to common infectious diseases such as tuberculosis (TB), in outbred populations. 

In 1996 I moved to the Medical Research Council Laboratories in The Gambia to investigate the genetic basis of susceptibility to TB. TB is a major public health problem globally, and although there is good evidence that host genetic factors are determinant of disease susceptibility it is not due to a single mutation. Thus larger more complex studies are required and we have studied the genetic basis of the immune responses required to contain TB, as well as clinical disease. We have identified associations between the genes encoding NRAMP1 (SLC11A1) and IL-1b and TB and identified possible immunological mechanisms by which variation in these genes may influence the host response to infection.  I am a co-investigator with the Wellcome Trust Case Control Consortium (WTCCC, www.wtccc.ac.uk) which was developed to conduct large scale association studies for common diseases.  We have recently conducted a genome wide association study in over 4000 TB cases and controls.

Genetic basis of immune responses to BCG and other vaccines given in early life
Infant vaccination is an excellent model in which to study the genetics of infectious diseases as vaccines such as BCG represent a controlled infection in which immunologically naive infants receive the same infecting dose of a well characterised antigen, and responses are measured at the same interval post vaccination in all infants. Furthermore, a major problem in the development of effective vaccines against childhood infections is the current inadequate understanding of the immune response in early infancy. Successful vaccination against all the major childhood pathogens will require detailed understanding of the basis of protective immunity and the response to immunisation in early life. We have characterised infant responses to neonatal BCG and a large twin study conducted in The Gambia has demonstrated that responses to BCG and other vaccines given in early life are genetically regulated. A Wellcome Trust Advanced Clinical Fellowship allowed me to conduct a genome scan in this twin cohort to identify chromosomal regions linked to immune responses. This work is ongoing.

Podoconiosis: a tropical model for gene-environment interactions?
Podoconiosis (non-infectious geochemical elephantiasis) is a chronic tropical disease that resembles filariasis.  Exposure to red alkalic clay soil, in individuals who cannot afford footwear, leads to the absorption of silicate particles.  These induce an inflammatory response in some, but not all, individuals: without intervention, chronic inflammation leads to lymphatic obstruction and of progressive, asymmetrical swelling of the lower legs.  Aside from the medical complications and disability that result, the disease is highly stigmatising within the community. 

Dr Gail Davey (School of Public Health, University of Addis Ababa, and Senior Clinical Research Fellow, BSMS) has been conducting studies on podoconiosis in the Wolaitta region of Ethiopia, where she observed that only a proportion of exposed individuals develop disease, and the disease clusters in families.  Multi-case family analysis estimated the heritability of podoconiosis to be 0.62 with a single major dominant gene as the ‘best-fit’ genetic model.  Thanks to a project grant from the Wellcome Trust, we are now conducting genetic studies to identify the gene involved.  Compared to other chronic diseases, the genetic basis of podoconiosis appears to be relatively simple and we hope lessons learnt from these studies will aid understanding of more complex gene environment interactions in other non-communicable diseases.

Conducting ethical genetic research in the community where podoconiosis is prevalent is not without its challenges.  It is one of the poorest regions of Ethiopia and few individuals have received any formal education.  Before enrolment begins, Fasil Tekola (an Ethiopian PhD student working on this project) has spent time in the Wolaitta region exploring issues around the consent process that are particular to the specific study area. Through analysis of interviews with members of the community, staff who proved health education and care to patients, and researchers involved with the project, we hope to develop a culturally sensitive method for informed consent.  This work is part of an ongoing collaboration with Professor Bobbie Farsides (BSMS Chair of Medical Ethics) and her colleague Dr Susie Bull.

Other activities

Brighton and Sussex University Hospitals Trust and BSMS have linked up with the University Teaching Hospital Lusaka and the School of Medicine, University of Zambia to foster collaboration in education, research and clinical practice.  The link has led to bilateral visits by practitioners from both countries, the exchange of medical students on clinical electives and a successful HIV Nurse education project funded through the joint DFID/British Council Development partnerships in Higher Education (DelPHE) scheme) www.britishcouncil.org/delphe-round-one-zambia-highlights.htm.

Key/recent publications:

Review articles and editorials:

Davey G, Tekola F, Newport MJ. Podoconiosis: non-infectious geochemical elephantiasis. Trans. R. Soc. Trop. Med. Hyg. 2007;101:1175-1180.
Davey G, Newport M. Podoconiosis: the most neglected tropical disease? Lancet 2007;369:888-889.
Newport MJ, Holland SM, Levin M, Casanova J-L. Inherited disorders of the interleukin-12-interferon gamma axis. In: Ochs HD, Smith E, Puck JM, editors. Primary Immunodeficiency Diseases. A Molecular and Genetic Approach. Oxford: Oxford University Press, 2006:390-401.
Newport MJ, Goetghebuer T, Marchant A. Hunting for immune response regulatory genes: vaccination studies in infant twins. Exp. Rev. Vaccines 2005;4:739-746.
Newport MJ. Genetic susceptibility to tuberculosis. Monaldi Arch. Chest Dis. 2004;61:102-111.
Newport MJ. The genetics of nontuberculous mycobacterial infection. Exp. Rev. Mol. Med. 2003;Feb28:2003:1-13.
Vekemans J, Ota MOC, Goetghebuer T, Newport MJ, Marchant A. Meeting report : Immunization of newborns in the tropics, The Gambia, 25-27 November, 1999. Vaccine 2001;19:387-392.

Marchant A, Newport MJ. Prevention of infectious diseases by neonatal and early infantile immunisation: prospects for the new millennium. Curr. Opin. Infect. Dis. 2000;13:241-246.

 

Original publications:
Davey G, GebreHanna E, Adeyemo A, Rotimi C, Newport M, Destas K. Podoconiosis: a tropical model for gene-environment interactions? Trans. R. Soc. Trop. Med. Hyg. 2007;101:91-96.

The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-678.

The Wellcome Trust Case Control Consortium, The Australo-Anglo-American Spondylitis Consortium (TASC). Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 2007;39:1329-1337.

Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF, Stevens HE, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007;450:877-892.

Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 2007;39:830-832.

Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 2007; in press.

Marchant A, Pihlgren M, Goetghebuer T, Weiss HA, Ota MOC, Schlegel-Hauter SE, et al. Predominant influence of environmental determinants on the persistence and avidity maturation of antibody responses to vaccines in infants. J. Infect. Dis. 2006;193:1598-1605.

Wilson JN, Rockett K, Keating B, Jallow M, Pinder M, Sisay-Joof F, et al. A hallmark of balancing selection is present at the promoter region of interleukin-10. Genes Immun. 2006;7:680-683.

Ota MOC, Goetghebuer T, Vekemans J, Okoko BJ, Newport MJ, McAdam KPWJ, et al. Dissociation between tuberculin skin test  and in vitro IFN-gamma responses following neonatal BCG vaccination. J. Trop. Paediatr. 2006;52:136-140.

Lee YC, Newport MJ, Goetghebuer T, Siegrist C-A, Weiss HA, Pollard AJ, et al. Influence of genetic and environment factors on the immunogenicity of Hib vaccine in Gambian twins. Vaccine 2006;24:5335-5340.

Awomoyi AA, Sirugo G, Newport MJ, Tishkoff SA. Global distribution of a novel trinucleotide microsatellite polymorphism (ATA)n in intron 8 of the SLC11A1 gene and susceptibility to pulmonary tuberculosis. Int. J. Hum. Genet. 2006;33:11-15.

Archer H, Vester U, van der Sande M, McAdam KPWJ, Hoyer P, Newport MJ. Oedema with proteinuria in Gambian children - a descriptive study. Pediatr. Nephrol. 2006;21:339-343.

Awomoyi AA, Charurat N, Marchant A, Miller EN, Blackwell JM, McAdam KPWJ, et al. Polymorphism in IL1B: IL1B -511 association with tuberculosis and decreased lipopolysaccharide-induced IL-1b in IFN-g primed ex-vivo whole blood assay. J. Endotox. Res. 2005;11:281-286.

Wilson JN, Rockett K, Jallow M, Pinder M, Sisay-Joof F, Newport M, et al. Analysis of IL10 haplotypic associations with severe malaria. Genes Immun. 2005;6:462-466.

Stensballe LG, Nante E, Jensen IP, Kofoed PE, Poulsen A, Jensen H, et al. Respiratory syncytial virus infection and BCG vaccination in Guinea-Bissau. Vaccine 2005;26:1251-1257.

Aliyu SH, Yong PFK, Newport MJ, Zhang H, Marriott RK, Curran MD, et al. Molecular diagnosis of Fusobacterium necrophorum infection (Lemierre's syndrome). Eur. J. Clin. Microbiol. Infect. Dis. 2005;24:226-229.

Dorman SE, Picard C, Lammas D, Heyne K, Baretto R, Rosenzweig SD, et al. Clinical features of dominant and recessive IFNg receptor 1 deficiencies. Lancet 2004;364:2113-2121.

Stockton J, Howson JMM, Awomoyi AA, Blackwell JM, McAdam KPWJ, Newport MJ. Polymorphism in NOD2, Crohn's disease and susceptibility to tuberculosis. FEMS Immunol. Med. Microbiol. 2004;41:157-160.

Newport MJ, Goetghebuer T, Weiss HA, Whittle H, Siegrist CA, Marchant A. Genetic regulation of immune responses to vaccines in early life. Genes Immun. 2004;5:122-129.

Newport MJ, Allen A, Awomoyi AA, Dunstan S, McKinney E, Marchant A, et al. The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis 2004;84:347-352.

Nejentsev S, Godfrey L, Snook H, Rance H, Nutland S, Walker N, et al. Comparative high-resolution analysis of linkage disequilibrium and haplotype tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. Hum. Mol. Genet. 2004;13:1633-1639.

Awomoyi AA, Nejentsev S, Richardson A, Hull J, Koch O, Podinovskaia M, et al. No association between interferon-g receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample. Thorax 2004;59:291-294.

Newport MJ, Awomoyi AA, Blackwell JM. Polymorphism in the interferon-gamma receptor-1 gene and susceptibility to pulmonary tuberculosis in The Gambia. Scand. J. Immunol. 2003;58:383-385.

Goetghebuer T, Ota MOC, Kebbeh B, John M, Jackson-Sillah D, Vekemans J, et al. Delay in motor development of twins in Africa: a prospective cohort study. Twin Res. 2003;6:279-284.

Allen A, Obaro S, Bojang K, Awomoyi AA, Greenwood BM, Whittle H, et al. Variation in Toll-like receptor-4 and susceptibility to group A meningococcal infection in Gambian children. J. Ped. Infect. Dis. 2003;22:1018-1019.

Sabeti P, Usen S, Farhadian S, Doherty T, Newport M, Pinder M, et al. CD40L association with protection from severe malaria. Genes Immun. 2002;3:286-291.

Ota M, Vekemans J, Schlegel S, Fielding K, Kidd M, Newport M, et al. Influence of Mycobacterium bovis bacillus Calmette-Guerin on antibody and cytokine responses to human neonatal vaccination. J. Immunol. 2002;168:919-925.

Lienhardt C, Bennett S, Del Prete G, Bah-Sow O, Newport M, Manneh K, et al. Investigation of environmental and host-related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design. Am. J. Epidemiol. 2002;155:1066-1073.

Koch O, Awomoyi A, Usen S, Richardson A, Hull J, Pinder M, et al. IFNGR1 promoter polymorphism and susceptibility to cerebral malaria. J. Infect. Dis. 2002;185:1684-1687.

Bennett S, Lienhardt C, Bah-Sow O, Aaby P, Manneh K, McAdam K, et al. The investigation of environmental and host-related risk factors for tuberculosis in Africa. II. The investigation of genetic factors. Am. J. Epidemiol. 2002;155:1074-1079.

Awomoyi AA, Marchant A, Howson JMM, McAdam KPWJ, Blackwell JM, Newport MJ. Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1) and susceptibility to tuberculosis. J. Infect. Dis. 2002;186:1808-1814.

Vekemans J, Amedei A, Ota MO, D'Elios MM, Goetghebuer T, Ismaili J, et al. Neonatal bacillus Calmette-Guerin vaccination induces adult-like IFN-g production by CD4 T lymphocytes. Eur. J. Immunol. 2001;31:1531-1535.

Marchant A, Goetghebuer T, Ota MO, Wolfe I, Ceesay SJ, De Groote D, et al. Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination. J. Immunol. 1999;163:2249-2255.

Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, et al. A mutation in the interferon-gamma receptor gene and susceptibility to mycobacterial infections in man. N. Engl. J. Med. 1996;335:1941-1949.

Jouanguy E, Altare F, Lamhamedi S, Revy P, Newport M, Levin M, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 1996;335:1956-1959.
Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J. Infect. Dis. 1996;174:878-880.

Newport M, Levin M, Blackwell JM, Shaw M-A, Williamson R, Huxley CM. Evidence against a mutation in NRAMP as the cause of familial disseminated mycobacterial infection in a Maltese kindred. J. Med. Genet. 1995;32:904-906.

Levin M, Newport MJ, D'Souza S, Kalabalikis P, Brown I, Lenicker H, et al. Familial disseminated atypical mycobacterial infection in early childhood: a human mycobacterial susceptibility gene? Lancet 1995;345:79-83.

Current/recent laboratory funding:

• The Wellcome Trust
• The British Lung Foundation
• The Association of Physicians of Great Britain and Ireland
• Medical Research Council (UK)
• Biotechnology and Biological Sciences Research Council (BBSRC)
• The Royal Society
• The Sir Halley Stewart Trust
  

Active collaborations:

• Dr Gail Davey, School of Public Health, Addis Ababa University, Ethiopia - Risk factors for podoconiosis (non-infectious geochemical elephantiasis)
• Dr Arnaud Marchant, Laboratory of Experimental Immunology, Universite Libre de Bruxelles, Belgium - Immune responses to neonatal BCG
• Dr Sergey Nejentsev, Cambridge Institute for Medical Research - Genetic susceptibility to TB in Russian populations
• Professors Paul Fine and Hazel Dockrell, London School of Hygiene and Tropical Medicine, and the Karonga Prevention Study, Chilumba, Malawi - Investigation of factors influencing immune responses to neonatal BCG in rural Malawi
• Dr Giorgio Sirugo - Genetic susceptibility to TB
• Professor Muntaser Ibrahim and Dr Hiba Mohammed, Institute of Endemic Diseases, Khartoum, Sudan - Genetic susceptibility to TB

Other information

• Executive Secretary of the African Society for Human Genetics
• Member of Council and Meetings Secretary for the Royal Society of Tropical Medicine and Hygiene
• Member of the Association of Physicians
• Member of the British Infection Society
• Member of the International Society for Infectious Diseases
• Associate Editor for the International Journal of Tuberculosis and Lung Disease
• Member of Scientific Committee, British Lung Foundation