Bacterial infection is the major cause of disability and death in children worldwide. We will use meningococcal disease (MD) as a model to understand genetic factors underlying susceptibility and severity of childhood bacterial infection which will then be applied to other childhood infections. We have established cohorts of patients with MD in Central and Southern Europe (CE,SE), UK and Africa as well as cohorts with other bacterial infections. We have established an inter-disciplinary team with expertise in Infectious Diseases, Immunogenetics, Bio-informatics, Microbiology, Public Health and Vaccinology including SME and industrial partners. We have already undertaken a genome wide study (GWAS) to identify genes causing susceptibility to meningococcal disease in a UK cohort. We identified complement factor H (fH) and fH-related (fHr) genes controlling MD susceptibility. This finding is fundamental to prevention as vaccines containing the MD fH receptor are undergoing trials. We will undertake GWAS on the CE, and SE MD cohorts, allowing meta analysis, and cross validation, and undertake GWAS on 2,500 Meningococcal Vaccine recipients. We will use next generation sequencing to identify the causal variants within the fH/fHr region and other regions implicated by pathway and severity analyses of the three MD GWAS and vaccine GWAS. We will match bacterial and host genetic variation and identify mechanisms of action of fH variants and other genes controlling susceptibility and severity using RNA expression, functional analyses and animal models. We will identify Mendelian defects and rare mutations as well as copy number variation and epi-genetic effects using next generation sequencing and RNA sequencing in “extreme phenotype” cohorts with MD , pneumococcal ,staphylococcal and salmonella disease. The study will identify mechanisms underlying susceptibility, provide new targets for treatment and prevention, and identify those at risk of disease or poor outcome.