EU FP-7 grant for Peter Hermans, Michiel van der Flier and Ronald de Groot

Peter Hermans

Bacterial infection is the major infectious cause of death in young children, accounting for over a quarter of all child deaths globally. Death from bacterial infection in children has persisted despite availability of antimicrobial agents and current childhood vaccines, highlighting the need for a better understanding of the inflammatory response to infection, for novel treatments of acute infection, for new methods to identify those at risk, and for better preventative strategies. There is now clear evidence that genetic factors are major determinants of both susceptibility and outcome of infectious diseases. Identification of the genes responsible, and the biological processes they control, is likely to be a powerful method for understanding the immunopathogenesis of childhood infection, and for identifying those in the population who are at risk of infection or poor outcome, thus enabling new treatment and preventative strategies.

In this 12 M€ consortium grant we aim to undertake a large-scale genomic study to identify the genes, and biological pathways they control, which determine susceptibility and severity in life-threatening bacterial infections of childhood in Europe and globally. We will build on an established EU collaboration which has brought together an interdisciplinary team of researchers with expertise in Paediatric Infectious Diseases and Intensive Care, Genetics, Immunology, Microbiology, Vaccinology, Bio-informatics and Public Health. We will utilise already established large and highly characterised cohorts of over 2,000 patients with meningococcal disease from Central Europe (CE) (the Netherlands, Austria, Germany, Switzerland), Southern Europe (SE) (Spain) and the UK, together with ethnically matched healthy controls (over 1,000). We also have access to databases and genotypic data from over 5,000 Caucasian controls genotyped through the Wellcome Trust Case Control Consortium (WTCCC). We have commenced recruitment of other cohorts of patients with life threatening bacterial infections from across Europe (pneumococcal, staphylococcal, and Gram negative sepsis) and West Africa (staphylococcal, pneumococcal and salmonella infections) as well as vaccine recipients (over 3,500 cases recruited). Unlike many purely DNA focused genetic studies, we have collected detailed clinical and pathophysiological information, RNA, plasma and serum from our cohorts, as well as infecting organisms and thus have established a unique resource to move beyond state-of-the-art genetics, to understand the biological mechanism through which genetic factors influence disease, and which brings together genetic and functional studies.

We will use meningococcal disease (MD) as the prototypic model to develop an integrated staged approach to identify the genetic basis of both susceptibility to infection and severity of disease in those affected, and then apply this model to the other major bacterial infections of childhood. Our approach aims to identify the complete range of genetic effects contributing to disease occurrence and outcome, by capturing rare Mendelian and major gene effects, as well as those due to common SNPs, copy number variation, splice defects, miRNA and epigenetic effects such as methylation. Our programme of work aims to identify individuals who are susceptible to infection or at risk of severe and fatal disease, to identify the genetic control of the host response; to enable development of targeted immunotherapy and biomarkers to predict severe disease, and to improve global vaccination efforts against these infections through better understanding of protective immunity and genetic control of vaccination responses.

Photo: Peter Hermans


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