The genetic basis of invasive meningococcal disease

Invasive meningococcal disease (IMD) is a rare disease affecting children and young adults due to bacterial infection by Neisseria meningitidis. Life-threatening infection of the blood, and/or brain lead to IMD. Although most people carry this bacteria in their nose, the majority do not develop IMD. We know that genetic mutations of specific immune pathways make individuals more susceptible to IMD. Patients with these mutations are unable to produce factors that help kill the bacteria. These mutations however are only present in a small number of IMD patients. We thus put forward the idea that other genetic mutations may exist in IMD patients. To identify new genes in IMD, we sequenced DNA from ~700 children with life-threatening bacterial infections, including 250 IMD patients. The sequences from these patients revealed mutations in other protective immune signaling pathways known to be involved in sensing invading bacteria. Here, we propose to test whether these new mutations affect the way a cell responds to the bacteria in an experimental infection. We will use cells from the lining of the airway, and blood cells. We chose to carry out these experiments in these cell types as airway cells are important for the entry of bacteria into the nose, and the blood cells will model the 'invasive' stage of disease when the bacteria replicates in the blood leading to life-threatening infection. Finally, we will test some of these mutations in a zebrafish model of bacterial infection where we may visualize how the body responds to infection in real-time. Understanding the role of
these genes will improve our understanding of why certain individuals develop life-threatening infections and may lead to better treatment and prevention of childhood infections.