Antibody gene variation and infectious disease susceptibility

Antibodies are fundamental to defence against a wide range of infectious agents and yet antibody responses vary markedly from individual to individual.

Although the reasons for this remain unclear, there is strong reason to suspect a role for immunoglobulin gene regions, not least because these are amongst the most variable in the human genome.

In earlier work, I linked the immunoglobulin heavy chain (IGH) locus to susceptibility to the most serious diseases caused by Streptococcus pyogenes, a major global health concern, and I now wish to determine the biological basis for this association.

This proposal therefore aims to test my hypothesis that common genetic variation in this locus impacts antibody-mediated immunity to S.pyogenes in a manner that alters disease susceptibility.

To do this, using an innovative high-throughput long-read sequencing approach, I will establish the extent and nature of germline IGH variation in children and adults with and without severe infection.

I will then assess the relationship between IGH variation and antibody-mediated immunity as well as susceptibility to severe infection.

Moving forward, I plan to use this approach to identify and prioritise antigens for rationale design of highly targeted vaccines and antibody-based therapeutics to combat a range of infectious diseases.