Hill group

Research overview

The group aim is to understand the genetic basis of susceptibility to different infectious diseases, especially mycobacterial tuberculosis and leprosy, severe respiratory infections including invasive pneumococcal disease and thoracic empyema (a suppurative bacterial infection of the pleural space, which occurs as a severe complication of pneumonia), as well as bacteraemia and sepsis. Host genetic factors play an important role in explaining inter-individual variation in susceptibility, although the current understanding of the specific host genetic factors which influence the development of these diseases is limited. Candidate gene studies have established a small number of replicated susceptibility loci for TB, leprosy, IPD, bacteraemia, and sepsis and the ongoing genome-wide association studies are hoped to improve the genetic understanding of these diseases.

Our studies have traditionally 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.

Since the rapid development in genotyping technologies, the group has also started to utilise genome-wide association and next generation sequencing approaches. As a part of the Wellcome Trust Case Control Consortium, we have conducted a large-scale genome-wide association study of tuberculosis including more than 2500 individuals from the Gambia. The study has provided insight into the role of host genetics in tuberculosis susceptibility as well as the genetic diversity of African populations.

Ongoing genome-wide association studies include the identification of genetic susceptibility loci for invasive pneumococcal disease (IPD), sepsis survival in Europe (GenOSept collaboration), bacteraemia susceptibility in Kenyan children as part of the Wellcome Trust Case Control Consortium 2, and HIV-1in Africa as part of the Trust Case Control Consortium 3. 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').

The research on invasive pneumococcal disease and empyema has been 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.

Identification of major susceptibility loci for these diseases is likely to have major implications for the study of other infectious and inflammatory disease processes and may translate into clinical benefit, for example through the discovery of novel therapeutic targets.