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 signalling 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.

Impact Summary

Economic and Societal Impact- Imperial College London, Industrial partners, UK NHS
Findings from this study may identify genes and pathways that may be amenable to therapeutic intervention not only for meningococcal disease but for other forms of sepsis. Despite the availability of the meningococcal vaccines, its long-term efficacy has not yet been determined. Although antibiotics remains an effective treatment course for IMD patients, novel therapeutics focusing on prevention or immuno-modulatory treatment would be of importance as antimicrobial resistance continues to be a problem. Not only will this generate revenue for Imperial College and Industrial partners, it will lessen the UK NHS burden due to hospitalizations due to meningococcal disease or sepsis.

Individual Impact- Patients and families with IMD or sepsis
Findings from this study will identify morbid genes in patients which will be explained to the patient. Patients will be re-contacted by an infectious disease constant as part of the BRC paediatric infectious disease clinic at St Mary's Hospital. The may also benefit from targeted treatment depending on the nature of the genetic mutation, or followed carefully by the specialty clinic to ensure proper treatment.